Background <p>This study investigated the clinical and molecular characteristics of <i>Staphylococcus aureus</i> (<i>S. aureus</i>) isolates from patients with coronavirus disease 19 (COVID- 19) at West China Hospital between December 1, 2022 and January 31, 2023.</p> Methods <p>In total, 102 strains isolated from sputum, bronchoalveolar lavage fluid, endotracheal aspirates, and blood were collected from 102 patients and subjected to multilocus sequence typing and antimicrobial susceptibility testing. Eighteen virulence genes were also analyzed by polymerase chain reaction.</p> Results <p>Seventy-five patients were discharged and 27 died. The predominant comorbidities were hypertension, diabetes mellitus, and cardiac disease. Twenty-eight known sequence types (STs) and 10 novel ones (ST8773/CC398, ST9221/CC5, ST9222/CC59, ST9223/CC8, ST9224/CC22, ST9225/CC1, ST9226/CC5, ST9227/CC59, ST9228/CC59, ST9229/CC398) were identified. The dominant molecular types were ST15 (CC15), ST59 (CC59), and ST5 (CC5). Among the three most prevalent STs, ST5 was significantly more resistant to levofloxacin, moxifloxacin, ciprofloxacin, and sulfamethoxazole than were ST59 and ST15. ST59 and ST5 had higher rates of resistance to erythromycin and clindamycin than ST15. All isolates contained at least eight virulence genes. The hemolysin gene <i>hlb</i> was found to be more prevalent in ST59 (100%) and ST5 (84.6%) than in ST15 (0) (<i>P</i> &lt; 0.001). The prevalence of the enterotoxin gene <i>seb</i> in ST59 (100%) was significantly higher than that in ST5 (23.1%) and ST15 (20%) (<i>P</i> &lt; 0.001), while the carrying rate of the <i>sec</i> gene was significantly higher in ST5 (76.9%) than that in ST59 (0) and ST15 (0) (<i>P</i> &lt; 0.001).</p> Conclusions <p>The <i>S. aureus</i> isolates from patients with COVID- 19 in Southwest China exhibited a high degree of genetic diversity. Different STs&#xa0;exhibited different antimicrobial resistance patterns and virulence gene carrying rates.</p>