Abstract Background Methicillin-susceptible Staphylococcus aureus (MSSA) infections are considered less severe than those caused by methicillin-resistant S. aureus. However, we have observed an important increase in severe cases of invasive MSSA infections in a hospital in Pereira, Colombia. Here, we characterize the clinical outcomes and epidemiology of these infections. Methods We included adult and pediatric patients hospitalized between February 2018 and April 2019 presenting with invasive infections caused by MSSA. All isolates were sent to a central laboratory to confirm identification. We determined cefazolin MICs at standard (105 CFU/mL) and high inoculum (107 CFU/mL) by broth microdilution and a rapid test to detect cefazolin inoculum effect (CIE). The CIE was defined as an increase of MIC to ≥16 µg/mL when tested at high inoculum. Clinical data (demographics, intensive care unit (ICU) admission, therapy and mortality) were obtained from medical records. Results A total of 60 patients were included in the study and 41.6% were women. Most (63.3%) infections were hospital-associated. Bacteremia was the most frequent type of infection (71.6%). The mean duration of hospital stay was 24.5 days (IQR, 14–44). 61.6% of patients were admitted to the ICU with a mean length of stay of 14 days (IQR, 7–30). Mortality at 30 days was 28.3% (17 out of 60 patients) and was slightly higher (30.2%) in patients with bacteremia. Early mortality (48 h) was 10% (n = 6). Most patients (75%) received β-lactams (28.8% cefazolin and 84% oxacillin). 18 patients (33%) had isolates that exhibited the CIE but most (n = 11) received oxacillin. Among 17 patients who died, 35% had received antibiotics other than β-lactams (5 vancomycin, 1 ampicillin-sulbactam) and two did not received any therapy due to rapid death. The mean duration of antibiotic therapy was 11 days. Source control was deemed appropriate in 65% of the cases. Conclusion An increase in severe invasive infections caused by MSSA was observed in our hospital with a high proportion of patients requiring ICU care. A significant proportion of patients received inappropriate treatment. Due to the aggressive nature of invasive MSSA infections, efforts to optimize appropriate therapy for these infections are urgently needed in Colombia. Disclosures All authors: No reported disclosures.