Objectives: We aimed to describe the prevalence, risk factors and outcomes of Methicillin-susceptible S. aureus (MSSA) community-acquired pneumonia (CAP) and compare them with those associated with CAP due to Streptococcus pneumoniae, the most frequent causative microorganism, in a large cohort of patients. Methods: This was an observational study of prospectively collected data of consecutive adults with CAP and a definitive etiology enrolled between 2004 and 2018. Patients were divided into MSSA CAP and pneumococcal CAP groups for analysis. Results: A microbial etiology was established in 1,548 (33%) cases: S. aureus caused 6% of microbiologically-confirmed CAP cases. In the latter, 52 were due to MSSA (60% of S. aureus CAP cases, and 3% of microbiologically-confirmed CAP cases) and 34 were due to MRSA (40% of S. aureus CAP cases, and 2% of microbiologically-confirmed CAP cases). S. pneumoniae was identified in 734 (47%) microbiologically-confirmed CAP cases. The presence of fever was independently associated with a lower risk of MSSA CAP (OR 0.53; 95% CI, 0.28–0.99). Patients with MSSA CAP had higher 30-day mortality than patients with pneumococcal CAP, both before and after adjustment for potential confounders (21% vs 7%, p = 0.002). MSSA was independently associated with 30-day mortality in the overall population. Conclusion: MSSA CAP was associated with worse outcomes than pneumococcal CAP in our cohort. MSSA was an independent factor of mortality.