The package insert of edoxaban for acute venous thromboembolism (VTE) recommended administration following initial parenteral anticoagulation including heparin. We explored the effectiveness and safety of edoxaban for acute VTE without initial heparin lead-in treatment. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients in Japan between January 2015 and August 2020. The current study population consisted of 1842 patients with acute VTE treated with edoxaban. The baseline characteristics and clinical outcomes were compared between the 2 groups with or without initial heparin lead-in treatment stratified by pulmonary embolism (PE) (848 patients) and deep vein thrombosis (DVT) only (994 patients). Propensity score (PS) matching analysis was performed to balance potential baseline differences. PE and DVT patients without heparin lead-in treatment accounted for 225 (27%) and 750 (75%), respectively. PS matching provided 195 pairs of PE patients and 224 pairs of DVT patients. There was no significant difference between the no heparin and heparin groups in the cumulative 30-day incidence of all-cause death (PE: 2.6% vs. 4.2%, P = 0.40; DVT: 2.7% vs. 3.2%, P = 0.78) and a composite of all-cause death, recurrent VTE, or major bleeding (PE: 5.8% vs. 8.4%, P = 0.32; DVT: 4.6% vs. 6.4%, P = 0.41). In the current real-world VTE registry, a substantial proportion of patients with acute VTE were treated with edoxaban without initial heparin lead-in treatment. There was no obvious signal suggesting worse short-term clinical outcomes with edoxaban treatment without versus with initial heparin lead-in treatment.