Background This study determines whether infection rates differ between prophylactic antibiotic use for patients with or without penicillin allergy before shoulder arthroplasty surgery. Methods Seven thousand one hundred forty primary shoulder arthroplasties operated between 2005 and 2016 were identified. We compared deep surgical site infection risk of patients who received perioperative vancomycin alone (6.2%, N = 444) or clindamycin alone (7.1%, N = 508) for penicillin allergy versus patients who received cefazolin alone without penicillin allergy (86.7%, N = 6,188). Results Seventy deep infections (1.2% 5-year cumulative incidence) were observed. The most common organism was Cutibacterium acnes (39.4%, N = 27). Compared with patients treated with cefazolin, infection risk was not different for those treated with vancomycin (hazard ratio = 1.17, 95% confidence interval 0.42 to 3.30, P = 0.8), but a higher risk of infection was identified for those treated with clindamycin alone (hazard ratio = 3.45, 95% confidence interval 1.84 to 6.47, P Conclusion A higher risk of postoperative infection is found after prophylactic use of intravenous clindamycin antibiotic after shoulder arthroplasty. Vancomycin is preferred over clindamycin for patients with penicillin allergy. Level of evidence III, retrospective cohort study.