Background Periprosthetic joint infection is a serious complication and a major reason for revision surgery after primary shoulder arthroplasty. The prophylactic antibiotics for primary shoulder arthroplasty that have predominantly been used in Sweden are cloxacillin and clindamycin. To address Cutibacterium acnes, benzylpenicillin has recently increasingly been added to cloxacillin, but it is unclear which antibiotic prophylaxis regimen is the most effective to prevent periprosthetic joint infection. Questions/purposes After controlling for baseline differences among patients such as age, gender, previous surgery, cement fixation, and arthroplasty type, was the risk of reoperation for infection higher in patients who received cloxacillin than in those who received clindamycin or the combination of benzylpenicillin and cloxacillin? Methods Data from the Swedish Shoulder Arthroplasty Register were used for this study. The inclusion criterion was registered antibiotic prophylaxis in primary arthroplasty. Between January 1, 1999, and December 31, 2019, 22,470 primary shoulder arthroplasties, including total shoulder, hemiarthroplasty, and reverse shoulder arthroplasties, were entered into the Swedish Shoulder Arthroplasty Register. Reporting of antibiotic prophylaxis to the register was introduced on January 1, 2013. Since then, the completeness of information on the type of antibiotic prophylaxis in the reports has been 85.3%. Consequently, 10,706 arthroplasties were eligible and fulfilled the inclusion criterion of reported antibiotic prophylaxis. A further 129 were excluded because of unusual prophylaxis regimens, leaving 10,577 shoulder arthroplasties for analysis. The Swedish Shoulder Arthroplasty Register gathers information from all 60 hospitals performing shoulder arthroplasty in Sweden, and through a comparison with the National Patient Register, it has been Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. Because this study was based on data collected from the National Quality Register to report any outcome as feedback to the users, no ethical permit was required. The National Ethical Review Board approved and confirmed this (decision 2022-01148-01).