<h3>Background</h3> Systemic lupus erythematosus (SLE) can result in impaired daily physical function through various mechanisms including active disease, chronic damage, and mental health symptoms that are common in the disease. However, the key drivers of reduced physical function are poorly understood, and no large-scale global studies investigating this have been conducted to date. <h3>Objectives</h3> To investigate key factors that contribute to impaired physical function in SLE globally. <h3>Methods</h3> SLE patients were identified from the COVAD 2 database, a global register of more than 20,000 respondents. Healthy controls (HC) were included to compare differences in physical function using the Patient Reported Outcome Measurement Information System (PROMIS) questionnaire. Demographics, medication, comorbidities, disease activity, Global Physical Health (GPH) and Global Mental Health (GMH) were collected. Multivariable regression analysis was used to identify contributing factors to favourable or poor physical function (measured by PROMIS Physical Function shortform PF-10a score). <h3>Results</h3> 979 SLE patients and 3358 HCs were included in analysis. Patients with SLE had significantly lower PF-10a score as compared to HCs (median 42, IQR 36-47 vs median 49, IQR 45-50, p&lt;0.0001). Determinants of physical function status in patients with SLE are summarised in Table 1. Briefly, factors associated with poor physical function included increasing age (-0.042, 95% CI -0.069 to -0.015, p=0.002) and methotrexate use (-0.928, 95% CI -1.844 to -0.012, p=0.047). Diabetes (-1.862, 95% CI -3.481 to -0.243, p=0.024) and interstitial lung disease (ILD) (-2.441, 95% CI -4.366 to -0.517, p=0.013), but not asthma or COPD, also contributed to lower PF-10a score. From a mental health perspective, anxiety (-0.970, 95% CI -1.853 to -0.087, p=0.031) but not depression contributed to a lower physical function score. Higher Pain Visual Analogue Scales (VAS) (-2.889, 95% CI -3.107 to -2.671, p&lt;0.001) and Fatigue VAS (-1.459, 95% CI -1.974 to -0.945, p&lt;0.001) also contributed to lower PF-10 scores. Hydroxychloroquine use (0.844, 95% CI 0.190 to 1.498, p=0.012) and higher GPH score (2.287, 95% CI 2.079 to 2.494, p&lt;0.001) were associated with favourable physical function. <h3>Conclusion</h3> Patients with SLE show significantly reduced physical function compared with HCs. Key contributors to poor physical function include intercurrent diabetes and ILD. Screening for, and aggressive early treatment of these conditions may confer improved long-term function. As expected, higher levels of pain and fatigue were associated with poor physical function. Methotrexate use was also identified as a contributing factor to reduced function, which could represent its use in articular manifestations that limit physical function. Importantly, use of hydroxychloroquine was associated with favourable physical function, adding to the well-recognised benefits of this drug in SLE. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Sook Yan Lee: None declared, Amelia Holloway: None declared, Elena Nikiphorou Speakers bureau: Has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly, Consultant of: Has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly, Grant/research support from: Holds research grants from Pfizer and Lilly, Ioannis Parodis Grant/research support from: Has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Naveen Ravichandran: None declared, Jessica Day Grant/research support from: Has received research funding from CSL Limited., Mrudula Joshi: None declared, Sreoshy Saha: None declared, Kshitij Jagtap: None declared, Wanruchada Katchamart: None declared, Phonpen Akarawatcharangura Goo: None declared, Binit Vaidya: None declared, Tsvetelina Velikova Speakers bureau: Has received speaker honoraria from Pfizer and AstraZeneca., Parikshit Sen: None declared, Samuel Katsuyuki Shinjo: None declared, Vishwesh Agarwal: None declared, Ai Lyn Tan Speakers bureau: Has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB., Consultant of: Has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB., Nelly Ziade Speakers bureau: Has received speaker fees, advisory board fees, and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre; none are related to this manuscript., Consultant of: Has received speaker fees, advisory board fees, and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre; none are related to this manuscript., Grant/research support from: Has received speaker fees, advisory board fees, and research grants from Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre; none are related to this manuscript., Marcin Milchert: None declared, Abraham Edgar Gracia-Ramos: None declared, Carlo Vinicio Caballero: None declared, Hector Chinoy Speakers bureau: Has received speaking fees from UCB and Biogen, Consultant of: Has received consulting fees from Novartis, Eli Lilly, Orphazyme, Astra Zeneca, Grant/research support from: Has received grant support from Eli Lilly and UCB. Was also supported by the National Institution for Health Research Manchester Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the NHS, National Institute for Health Research, or Department of Health., Vikas Agarwal: None declared, Rohit Aggarwal Consultant of: Consultant of: Mallinckrodt, Octapharma, CSL Behring, Bristol. Myers-Squibb, EMD Serono, Q32, Kezar, Pfizer, AstraZeneca, Alexion, Argenx, Boehringer Ingelheim (BI), Corbus, Janssen, Kyverna, Roivant, Merck, Galapagos, Actigraph, Scipher, Horizon Therapeutics, Teva, Beigene, ANI Pharmaceuticals, Biogen, Nuvig, Capella Bioscience, CabalettaBio., Grant/research support from: Grant/research support from: Mallinckrodt, Pfizer, Bristol Myers-Squibb, Q32, EMD Serono, Janssen, Boehringer Ingelheim (BI), Latika Gupta: None declared, Chris Wincup: None declared.