There is continued controversy regarding the optimal venous thromboembolism (VTE) prophylaxis, particularly for total joint arthroplasty (TJA) patients at higher risk. The purpose of this study was to compare the efficacy of aspirin (ASA) to warfarin in patients with higher risk of VTE.This retrospective study examined 30,270 patients who received ASA or warfarin for VTE prophylaxis after TJA. Using a previously developed risk stratification model, patients were classified into low or high VTE risk categories. Postoperative 90-day VTE, periprosthetic joint infection (PJI), gastrointestinal complications, and mortality were recorded.The incidences of VTE, PJI, and mortality were higher in patients receiving warfarin compared to ASA. In multivariate analysis, warfarin was an independent risk factor for VTE, PJI, and mortality in the higher risk VTE patients (P < .001). There was no significant difference in gastrointestinal complications between groups.Our study demonstrates that ASA is as effective as and safer than warfarin for VTE prophylaxis after TJA, even in patients at higher risk of VTE.