Objective To analyze the clinical drug-sensitivity results, types of drug resistance Staphylococcus aureus  (S.aureus)  isolated from the patients of nosocomial infection and risk factors for nosocomial infection over two years, and to explore its reference value in clinical control of the occurrence of drug-resistant S. aureus, hospital infection and rational application of antimicrobial drugs.  Methods  The clinical characteristics and drug resistance of drug-resistant S. aureus isolated in 2020-2021 were analyzed, and independent risk factors of nosocomial infection caused by drug-resistant S. aureus were explored using univariate and logistic regression.  Results  Multi-drug resistant S. aureus accounted for 49.7% (69/139), MRSA (methicillin-resistant Staphylococcus aureus) strains accounted for 41.0% (57/139), β-lactamase-producing strains accounted for 72.7% (101/139), and clindamycin-induced resistant strains accounted for 15.1% (21/139). S. aureus was mainly isolated from respiratory and wound infection sites (36.0% and 48.9%), and it had a high rate of resistance to a variety of antimicrobial drugs, with 100% sensitivity to vancomycin and tigecycline, the sensitivity rate to linezolid and chloramphenicol was 99.28% and 93.85%. Regression analysis showed an OR of 3.184 for invasive manipulation, with a P value < 0.05.  Conclusion   S. aureus was mainly isolated from wound site specimens, with a high occupancy of clinical multi-drug resistant bacteria, mostly MRSA and β-lactamase-producing strains, and a high prevalence of common antibiotic resistance. Invasive manipulation was an independent risk factor for drug-resistant S. aureus infection.