S. aureus bacteremia is associated with high mortality. The aim was to identify predictors of mortality among patients with S. aureus bacteremia and evaluate the role of early source control. This retrospective study was conducted at the Lausanne University Hospital, Switzerland. All episodes of S. aureus bacteremia among adult patients from 2015 to 2021 were included. During the study period, 839 episodes of S. aureus bacteremia were included, of which 7.9% were due to methicillin-resistant isolates. Bacteremias were related to bone or joint infections (268; 31.9%), followed by bacteremia of unknown origin (158; 18.8%), proven endocarditis (118; 14.1%) and lower-respiratory tract infections (79; 9.4%). Overall 28-day mortality was 14.5%. Cox multivariate regression model showed that Charlson comorbidity index > 5 (P < 0.001), nosocomial bacteremia (P 0.019), time to blood culture positivity ≤ 13 h (P 0.004), persistent bacteremia for ≥ 48 h (P 0.004), sepsis (P < 0.001), bacteremia of unknown origin (P 0.036) and lower respiratory tract infection (P < 0.001) were associated with 28-day mortality, while infectious diseases consultation within 48 h from infection onset (P < 0.001) was associated with better survival. Source control was warranted in 575 episodes and performed in 345 episodes (60.0%) within 48 h from infection onset. Results from a second multivariate analysis confirmed that early source control (P < 0.001) was associated with better survival. Mortality among patients with S. aureus bacteremia was high and early source control was a key determinant of outcome. Infectious diseases consultation within 48 h played an important role in reducing mortality.