Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by heterogeneous pathogenesis, various clinical manifestations, and a broad spectrum of autoantibodies which recognize different cellular components. This study examines the clinical significance and serological associations of serum antiribosomal P antibodies (anti-P) derived from SLE patients in a population from southwestern Colombia. Methods We performed a cross-sectional study of 66 SLE patients. Serum antiribosomal P0 autoantibodies were detected by line immunoassay using the ANA-LIA MAXX kit and processed on the automated HumaBlot 44FA system (Human Diagnostics, Germany). Results Of the 66 SLE patients included in the study, 17 patients (25.76%) showed anti-P positivity by line immunoassay (IA), 47 (71.21%) were negative, and results from 2 patients were indeterminate. We did not find an association with neuropsychiatric SLE (NPSLE), renal, or hepatic disorders (P > 0.05). Laboratory findings indicated that anti-P positivity was significantly associated to anti-Smith (P = 0.001), anti-Ro60/SSA (P = 0.046), and anti-dsDNA antibodies (P = 0.034), the latter being true only when performed using indirect immunofluorescence (IIF). Conclusion The anti-P antibodies are not associated with clinical manifestations such as NPSLE, lupus nephritis, or hepatic involvement in the southwest Colombian SLE population. Moreover, we confirmed previously reported association between anti-P antibody, serum anti-dsDNA, and anti-Smith.