Background Preoperative antibiotic prophylaxis remains one of the most important strategies for prevention of postoperative infection. In patients with penicillin allergy, alternative medications such as vancomycin are often used despite reduced antimicrobial coverage and recent literature questioning the efficacy of vancomycin monotherapy. Questions/purposes (1) Are patients who receive vancomycin alone for penicillin allergy at greater odds of developing surgical site infection (SSI) as compared with patients who receive cefazolin for prophylaxis before total joint arthroplasty (TJA) without a patient-reported allergy? (2) What organism profile is associated with vancomycin monotherapy?Methods We performed a retrospective study of 10,391 primary TJAs performed between 2005 and 2014 at two institutions with a minimum of 1-year followup. Patients reporting penicillin or cephalosporin allergy were electronically queried from the anesthesia note. The odds of deep SSI and causative organisms were compared using multivariate analysis between b-lactam-allergic patients receiving vancomycin and nonallergic patients receiving cefazolin. Results After controlling for potential confounders, including comorbidities, we found that vancomycin alone did not affect the odds of deep SSI development (adjusted odds ratio [OR], 0.98; 95% confidence interval [CI], 0.67-1.43; p = 0.907). Although the overall odds of deep SSI were not different for patients receiving vancomycin versus cefazolin, we found that vancomycin was associated with a reduced risk of infection with Gram-positive organisms (adjusted OR, 0.25 [CI,; p = 0.003) and antibiotic-resistant organisms (adjusted OR, 0.10 [CI,