Abstract Background Direct oral anticoagulants (DOACs) including edoxaban are currently widely used all over the world. Each DOAC has a specific usage for the treatment and second prevention of venous thromboembolism (VTE) in the acute phase as well as in the chronic phase. Edoxaban is recommended to be administered after an appropriate initial treatment including parenteral anticoagulation therapy such as heparin. However, because of the rapid anticoagulant effect of edoxaban after oral intake, some physicians could administer edoxaban initially without parenteral anticoagulation therapy in the daily clinical practice, which has not been investigated so far. Purpose The purpose of this study is to explore the effectiveness and safety of edoxaban treatment for VTE without initial parenteral anticoagulation therapy. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. Of those, 1842 patients received edoxaban including 848 patients with pulmonary embolism (PE) and 994 patients with deep vein thrombosis (DVT) alone, who were divided into 2 groups based on the presence or absence of initial parenteral anticoagulation therapy with heparin. Propensity score matching (PSM) was performed to adjust for potential baseline differences in the 2 groups. Results PE and DVT patients with initial parenteral anticoagulation therapy with heparin accounted for 623 (73.5%) and 244 (24.5%), respectively. After the PSM, 195 pairs of PE patients and 226 pairs of DVT patients were matched. In PE patients, those matched by the PSM were relatively mild cases compared to the unmatched cases (simplified PESI score=0: 25.9% vs. 12.4%, P<0.001). Whereas, in DVT patients, those matched were relatively severe cases compared to unmatched cases (isolated distal DVT: 24.1% vs. 71.0%, P<0.001). In the matched cohort, there was no significant difference in baseline characteristics between the 2 groups, including simplified PESI score in PE patients and thrombus location profile in DVT patients. In both PE patients and DVT patients, the 30-day cumulative incidences of all-cause death were not significantly different between the 2 groups (PE patients: 3.7% vs. 2.6%, P=0.56; DVT patients: 2.7% vs. 4.5%, P=0.31). Similarly, the 30-day cumulative incidences of recurrent VTE and major bleeding were not significantly different between the 2 groups (recurrent VTE: PE patients: 0% vs. 0.5%, P=0.32; DVT patients: 0.6% vs. 0.9%, P=0.99; major bleeding: PE patients: 1.5% vs. 3.2%, P=0.32; DVT patients: 2.2% vs. 3.2%, P=0.54) Conclusion In this current real-world VTE registry, a certain number of patients received edoxaban without parenteral anticoagulation therapy, who did not show a signal of worse clinical outcomes.