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Introduction: Staphylococcus aureus (S. aureus) is an important pathogen in both community-acquired and hospital-acquired pneumonia. S. aureus pneumonia has a high mortality rate and serious complications. Resistance to multiple antibiotics is a major challenge in the treatment of S. aureus pneumonia. Understanding the antibiotic resistance profile of S. aureus and the risk factors for mortality can help optimize antibiotic regimens and improve patient outcomes in S. aureus pneumonia., Methods: A prospective cohort study of 118 patients diagnosed with S. aureus pneumonia between May 2021 and June 2023 was conducted, with a 30-day follow-up period. Demographic information, comorbidities, Charlson Comorbidity Index, clinical characteristics, outcomes, and complications were collected for each enrolled case. The data were processed and analyzed using R version 3.6.2., Results: S. aureus pneumonia has a 30-day mortality rate of approximately 50%, with complication rates of 22% for acute respiratory distress syndrome (ARDS), 26.3% for septic shock, and 14.4% for acute kidney injury (AKI). Among patients with methicillin-resistant S. aureus (MRSA) pneumonia treated with vancomycin (n = 40), those with a vancomycin minimum inhibitory concentration (MIC) ≤ 1 had significantly higher cumulative survival at day 30 compared to those with MIC ≥ 2 (log-rank test p = 0.04). The prevalence of MRSA among S. aureus isolates was 84.7%. Hemoptysis, methicillin resistance, acidosis (pH < 7.35), and meeting the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria for severe pneumonia were significantly associated with mortality in a multivariate Cox regression model based on the adaptive least absolute shrinkage and selection operator (LASSO)., Conclusions: S. aureus pneumonia is a severe clinical condition with high mortality and complication rates. MRSA has a high prevalence in Can Tho City, Vietnam. Hemoptysis, methicillin resistance, acidosis (pH < 7.35), and meeting the IDSA/ATS criteria for severe pneumonia are risk factors for mortality in S. aureus pneumonia., (© 2024. The Author(s).)