OBJECTIVE The risks of venous thromboembolism (VTE) and bleeding with direct oral anticoagulants (DOACs) and aspirin for thromboprophylaxis after orthopedic surgery were studied. METHODS A single center, retrospective study was conducted to examine patients who underwent a major orthopedic surgery from 2011 to 2015. The primary endpoint evaluated was the net clinical outcome of bleeding and thrombosis rates between the DOAC and aspirin groups. Secondary endpoints included bleeding rates, thrombosis rates, transfusion rates, and 90-day readmission rates. The primary endpoint was analyzed using adjusted logistic regression model with propensity score added as an independent variable. RESULTS A total of 420 patients were included in this study. The proportion of patients with composite primary outcome was similar between the groups (12.9% and 13.3%, in the DOAC and aspirin groups, respectively; p > 0.5). VTE events were numerically lower in the DOAC group, but the result was not statistically significant. Readmission due to VTE or bleeding and bleeding events were also similar between the groups. The DOAC group had a higher proportion of blood transfusions of at least 2 units of blood postoperatively compared with the aspirin group (p = 0.04). CONCLUSIONS No difference in net clinical outcome was observed in patients who received a DOAC or aspirin for VTE prophylaxis after major orthopedic surgery.