Background: Prophylactic antibiotics decrease surgical site infection (SSI) rates, and their timing, choice, and discontinuation are measured and reported as part of the Surgical Care Improvement Project (SCIP). The aim of this study was to assess the comparative effectiveness of the SCIP-approved antibiotics for SSI prevention. Methods: This retrospective cohort study utilized national Veterans Affairs (VA) data on patients undergoing elective hip or knee arthroplasty from 2005 to 2009. Data on prophylactic antibiotics were merged with VA Surgical Quality Improvement Program data to identify patient and procedure-related risk factors for SSI. Patients were stratified by documented penicillin allergy. Chi-square and Wilcoxon rank-sum tests were used to compare SSI rates among patients receiving SCIP-approved prophylactic antibiotics. Results: A total of 18,830 elective primary arthroplasties (12,823 knee and 6007 hip) were included. Most patients received prophylactic cefazolin as the sole agent (81.9%), followed by vancomycin as the sole agent (8.0%), vancomycin plus cefazolin (5.6%), and clindamycin (4.5%). Documented penicillin allergy accounted for 54.1% of cases involving vancomycin administration compared with 94.6% of cases involving clindamycin. The overall thirty-day SSI rate was 1.4%, and the unadjusted rate was 2.3% with vancomycin only, 1.5% with vancomycin plus cefazolin, 1.3% with cefazolin only, and 1.1% with clindamycin. Unadjusted analysis of penicillin-allergic patients revealed an SSI rate of 2.0% with vancomycin only compared with 1.0% with clindamycin (p = 0.18). For patients without penicillin allergy, the SSI rate was 2.6% with vancomycin only compared with 1.6% with vancomycin plus cefazolin (p = 0.17) and 1.3% with cefazolin only (p < 0.01). Conclusions: Current SCIP guidelines address antibiotic timing but not antibiotic dosage. (The generally accepted recommendation for vancomycin is 15 mg/kg.) Although vancomycin is a narrower-spectrum antibiotic than either cefazolin or clindamycin, our finding of higher SSI rates following prophylaxis with vancomycin only may suggest a failure to use an appropriate dosage rather than an inequality of antibiotic effectiveness. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.