ObjectivesThis paper aims to determine the Staphylococcus aureus bacteremia (SAB) in-hospital mortality rate and its associated risk factors during the COVID-19 pandemic. MethodsA total of 167 SAB samples were collected between March 2020 and March 2022 at a teaching hospital in Tehran, Iran. The patient's baseline data and antibiograms were collected. The outcome of the study was in-hospital mortality. ResultsThe overall in-hospital mortality rate was 41.9 %, with higher mortality observed in patients over 60 years old (P = 0.032), those with community-acquired Staphylococcus aureus bacteremia (P = 0.010), and those admitted to the ICU (P = 0.016). Antibiotic resistance profiles indicated a higher mortality in resistant S.aureus strains but only significant for ciprofloxacin (P = 0.001), methicillin (P = 0.047), and sulfamethoxazole (P = 0.023). Multivariate analysis identified age, sex, ICU admission, and the source of bacteremia as independent predictors of mortality, while COVID-19 coinfection and resistance to antibiotics were not found to be significant predictors. ConclusionSAB remains a challenging infection that is amplified by the pandemic. Older age and ICU admission are significant mortality predictors. In settings with a high prevalence of MRSA, factors like age, sex, and quality of care outweigh pathogen-related factors such as antibiotic resistance.