Prophylactic anticoagulation with enoxaparin 40 mg once daily for a prolonged period of time after radical cystectomy reduces the risk of venous thromboembolism (VTE). To boost compliance, we switched from protracted anticoagulation alternatives to direct oral anticoagulants (DOAs; eg apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily). In this study, researchers evaluated the effectiveness of DOAs for long-term VTE prophylaxis. All patients who received a radical cystectomy at their facility between January 2007 and June 2021 were included in this retrospective analysis. To determine whether or not prolonged DOAs are comparable to enoxaparin in terms of VTE events and risk of gastrointestinal bleeding, multivariable logistic regression models were developed. It was found that the median age of 657 patients was 71. The proportion of patients given rivaroxaban/apixaban as part of extended VTE prevention was 45.5% (46/101). About 40 patients (7.4%) who did not receive prolonged prophylaxis on discharge developed a VTE over the 90-day follow-up period, while only 2 patients (3.6%) in the enoxaparin group and 0 patients (P=0.11) in the DOA group did so. Seven patients (1.3% of the total) who did not receive extended anticoagulation experienced gastrointestinal bleeding, while none of the patients in the enoxaparin group and just 1 patient in the DOA group experienced such bleeding (P=0.60). Enoxaparin (OR 0.33, P=0.09) and DOAs (OR 0.19, P=0.15) were both associated with similar decreases in the risk of experiencing VTE compared to controls on multivariable analysis. This early evidence suggests that oral apixaban and rivaroxaban are safe and effective alternatives to enoxaparin.