In this large, prospective, multicenter, open-label randomized controlled trial, 1901 high-risk patients undergoing primary total joint arthroplasty were randomized across 17 U.S. centers into four groups: vancomycin powder alone, dilute povidone-iodine lavage alone, combined vancomycin–povidone-iodine protocol, or saline control. The cohort included 821 total hip arthroplasties (THA) and 1080 total knee arthroplasties (TKA). The primary outcomes were 3-month rates of periprosthetic joint infection (PJI) and wound complications, aseptic and septic revisions, emergency department visits, readmissions, and serious adverse events. Overall, the results of the study revealed no statistically significant differences among the four groups for infection rates, wound complications, revisions, emergency visits, or readmissions after either hip or knee arthroplasty. These findings suggest that, in high-risk patients, adding vancomycin powder, dilute povidone-iodine lavage, or both does not confer measurable short-term benefit over saline irrigation alone.