4,239 patients undergoing an arthroplasty surgery were randomized to received infection prophylaxis with vancomycin and cefazolin (n=2,118) or cefazolin alone (n=2,121). The primary outcome of interest was the incidence of surgical site infection at 90 days post-operation. Secondary outcomes of interest included superficial, deep, and organ-space infection; deep or organ-spaced infections between 90-180 days; surgical-site infections with methicillin-resistant staphylococcus species, and safety outcomes. The incidence of surgical-site infection not significantly different between the vancomycin-cefazolin combination group and the cefazolin group. The combination group reported significantly higher rates of hypersensitivity reaction, and a higher rate of superficial surgical-site infection in knee arthroplasty patients. No other between-group differences were observed.