Many adult patients with Fontan circulation are treated with antithrombotic agents, including direct oral anticoagulants (DOACs). However, few studies have investigated the efficacy, feasibility, and safety of DOACs in adult patients with Fontan circulation. In this retrospective cohort study, clinical records of 139 adult patients with Fontan circulation (70 females, 50.4%) from April 2015 to March 2018 were reviewed and classified into five groups according to the therapeutic agents used: DOAC (n = 36), vitamin K antagonist (VKA; n = 41), antiplatelet drug (n = 43), combination of an antiplatelet and anticoagulant (n = 14), and no-antithrombotic prophylaxis (n = 5). In a 1114-patient-year follow-up, 28 major events occurred, including 10 thrombotic and 18 bleeding events; 11 of 18 (61%) female patients had severe menorrhagia. The incidence (% patient-years) of major events was 0.6, 1.42, 3.74, and 5.13 in the DOAC, antiplatelet, VKA, combination, and no-antithrombotic groups, respectively. The Cox proportional hazards analysis revealed that the DOAC group had a lower rate of primary endpoints than the VKA group in males. DOAC may be a safe antithrombotic agent for use in adult patients with Fontan circulation, particularly in males. However, these findings should be confirmed in multi-institutional prospective studies. • Many of adult patients with Fontan circulation are treated with antithrombotic agents. • Antithrombotic therapy in adult Fontan patients has not been established. • Retrospective study of the efficacy and safety of anti-thrombosis including DOACs. • DOAC may be a safe antithrombotic agent in adult patients with Fontan Circulation, particularly in males. • However, these findings should be confirmed in multi-institutional prospective studies. [ABSTRACT FROM AUTHOR]