We evaluated the epidemiological and molecular features of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and methicillin-sensitive S. aureus (MSSA) from children and adult patients with skin and soft-tissue infections (SSTIs) in China. Prospective community-acquired S. aureus SSTI surveillance was conducted in 23 hospitals over a 24-month period. Susceptibility to 16 antimicrobials was evaluated using the agar dilution method. StatApriori was used to determine statistically significant association trends. The genotypic characteristics of CA-MRSA isolates were tested by staphylococcal cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) typing, and multilocus sequence typing. The presence of Panton-Valentine leukocidin (pvl) genes was determined. Overall, 71.6% (1946/2716) of cases were community-associated S. aureus. CA-MRSA accounted for 2.6% (51). Out of 1895 methicillin-sensitive S. aureus strains, 97.3% were resistant to erythromycin, 96.6% to penicillin and 89.1% to clindamycin. No S. aureus strains were resistant to vancomycin. Thirteen sequence types (STs) and 17 spa types were detected among the CA-MRSA strains. The most prevalent sequence type was ST121 (19/51, 37.3%), followed by ST59 (13/51, 25.5%). In addition, t437 was predominant, accounting for 43.1% (22/51). Only five (9.8%) of the CA-MRSA strains harbored pvl genes. There were no significant differences in antibiotic sensitivity profiles between ST121 and non-ST121 MRSA isolates. However, ST121 strains tended to be more resistant to cefazolin, whereas non-ST121 strains were more resistant to chloramphenicol. In conclusion, CA-MRSA infections are rare among Chinese SSTI patients. MRSA strains in China have diverse genetic backgrounds, with ST121 being the predominant clone. Fusidic acid and mupirocin remain effective for topical treatment.