Background: Direct oral anticoagulants (DOACs), including edoxaban, rivaroxaban, and apixaban, are administered for the treatment of venous thromboembolism (VTE) in Japan. However, only a few reports have compared the effectiveness and safety of these DOACs. Methods and Results: We retrospectively enrolled 702 patients who received DOACs for VTE treatment between September 2014 and March 2020. We investigated patient demographics, VTE recurrence, major bleeding, and mortality until March 2021, and compared them among the 3 DOACs. Most patients (similar to 70%; n=496) were prescribed edoxaban, followed by apixaban (n=107) and rivaroxaban (n=99). Age, body mass index, renal function, and the proportion of cancer patients did not differ significantly among the DOACs. Edoxaban was administered relatively more in women with low body weight and anemia. The rate of pulmonary embolism was significantly lower among patients receiving edoxaban than apixaban or rivaroxaban (24.4% vs. 41.1% and 53.5%, respectively). VTE reoccurred in 2 patients administered apixaban and 1 patient administered edoxaban. The cumulative incidence of major bleeding at 1 year was 11.7%, 18.5%, and 9.0% in the edoxaban, apixaban, and rivaroxaban groups, respectively. There were no significant differences in the cumulative incidence of major bleeding and all-cause death, estimated by Kaplan-Meier analysis, among the DOACs (log-rank P=0.316 and 0.722, respectively). Conclusions: The safety of the 3 DOACs did not differ significantly in clinical settings, despite differences in patient demographics.