Aprotinin therapy is a promising strategy for reducing blood loss and blood transfusion requirements. The efficacy and safety of aprotinin in orthopedic surgery, however, remain controversial. We searched electronic databases for randomized controlled trials on the efficacy and safety of the use of aprotinin in orthopedic surgery. Thirteen trials that included a total of 506 patients who underwent major orthopedic surgery were analyzed. The pooled intraoperative and perioperative blood loss was significantly less in the aprotinin-treated patients than in the control patients (weighted mean difference [WMD] for intraoperative blood loss = -229 mL, 95% confidence interval [CI] = -367 to -91 mL, P = 0.0011; WMD for perioperative blood loss = -557 mL; 95% CI = -860 to -254 mL; P < 0.0001). The pooled amounts of red blood cell (RBC) units (U) transfused intraoperatively and perioperatively were significantly less in the aprotinin-treated patients than in the control patients (WMD for intraoperative RBC U = -1.1 U; 95% CI = -1.7 to -0.4 U; P = 0.0001; WMD for perioperative RBC U = -1.1 U; 95% CI = -1.7 to -0.5 U; P < 0.0001). Aprotinin was not associated with an increased incidence of deep vein thrombosis (odds ratio = 0.39; 95% CI = 0.14 to 1.05, P = 0.061). The authors conclude that aprotinin reduces the intraoperative and perioperative blood loss and allogeneic blood transfusion requirement and may not be associated with increased risk of deep vein thrombosis in the presence of pharmacological or mechanical prophylaxis in patients undergoing major orthopedic surgery.