BACKGROUND Inherited deficiencies in antithrombin (AT), protein C (PC), and protein S (PS) increase the risk of venous thromboembolism (VTE). The efficacy and safety of direct oral anticoagulants (DOACs) in severe VTE cases after mechanical thrombectomy are uncertain. This study aimed to evaluate the use of DOACs combined with mechanical thrombectomy in 55 patients with VTE, including 11 patients with confirmed deep vein thrombosis (DVT) and pulmonary thromboembolism (PE), 27 patients with DVT alone, and 17 with pulmonary thromboembolism alone, from a single center between January 2016 and December 2023. MATERIAL AND METHODS All patients with symptomatic VTE confirmed by computed tomography underwent mechanical thrombectomy. Fourteen patients with reduced AT (n=4), PC (n=6), and PS (n=4) function were classified as group 1, while the remaining 41 without thrombophilia were classified as group 2. The outcomes, including recurrent VTE, bleeding events, and all-cause mortality, were compared between patients with and without thrombophilia. RESULTS DOAC use was similar between the groups. One patient in the thrombophilia group switched DOACs due to bleeding, while 7 in the non-thrombophilia group changed due to bleeding or recurrent VTE. Recurrent VTE was higher in the non-thrombophilia group (7.1% vs 17.1%; P=0.664), while bleeding events were more frequent in the thrombophilia group (35.7% vs 17.1%; P=0.259); however, neither difference was statistically significant. All-cause mortality was similar between groups (7.1% vs 6.7%; P=0.903). CONCLUSIONS The study found no difference in the efficacy and safety of DOACs between VTE patients with and without inherited thrombophilia undergoing mechanical thrombectomy.