Objective To analyze the distribution characteristics and antimicrobial resistance of pathogens causing periprosthetic joint infection (PJI) after hip and knee arthroplasty, and provide reference for clinical prevention and rational use of antimicrobial agents. Methods Clinical data of patients with PJI after hip and knee arthroplasty in a hospital from January 2020 to December 2022 were retrospectively collected and analyzed. Distribution of pathogens and resistance to commonly used antimicrobial agents were analyzed. Results A total of 105 patients with PJI after joint arthroplasty were included in the analysis. There were 67 and 38 cases underwent hip and knee arthroplasty, respectively. A total of 124 strains of pathogenic bacteria were detected, with Gram-positive strains accounting for 74.19% (n=92), followed by Gram-negative bacteria (16.13%, n=20). The most common pathogen was Staphylococcus aureus (37.90%, n=47) and coagulase-negative Staphylococcus (22.58%, n=28). Antimicrobial susceptibility testing result showed that among Gram-positive coccus, resistance rates of Staphylococcus aureus and coagulase-negative Staphylococcus to oxacillin were 26.67% and 73.08%, respectively, while both were sensitive to vancomycin. Resistance rates of Gram-negative bacteria to ciprofloxacin, piperacillin/tazobactam, and ceftriaxone were 33.33%, 41.18%, and 55.56%, respectively, while sensitive to meropenem. Conclusion Staphylococcus aureus and coagulase-negative are the main pathogens causing PJI after joint arthroplasty, the latter has a higher resistance rate to oxacillin. Empirical treatment may be effective for Staphylococcus aureus PJI, but not sufficient for coagulase negative Staphylococcus PJI.