AIMS : To compare the risk of all-cause mortality, stroke, and bleeding in patients with atrial fibrillation (AF) and valvular heart disease (VHD) treated with vitamin K antagonist (VKA) or factor Xa-inhibitors (FXa-I; rivaroxaban and apixaban). METHODS AND RESULTS : We cross-linked data from Danish nationwide registries identifying patients with AF and VHD (aortic stenosis/insufficiency, mitral insufficiency, bioprosthetic heart valves, mitral-, and aortic valve repair) initiating VKA or FXa-I between January 2014 and June 2017. Outcomes were all-cause mortality, stroke, and bleeding. Using cause-specific Cox regression, we reported the standardized absolute 2-year risk of the outcomes and absolute risk differences (ARD). We identified 1115 (41.7%), 620 (23.1%), and 942 (35.2%) patients initiating treatment with VKA, rivaroxaban, and apixaban, respectively. The standardized absolute risk (95% confidence interval) of all-cause mortality associated with VKA treatment was 34.1% (30.4-37.8%) with corresponding ARD for FXa-I of -2.7% (-6.7% to 1.4%). The standardized absolute risk of stroke for VKA was 3.8% (2.2-5.4%) with corresponding ARD for FXa-I of -0.1% (-2.0% to 1.8%). The standardized risk of bleeding for VKA was 10.4% (7.2-12.9%) with corresponding ARD for FXa-I of -2.0% (-5.1% to 1.1%). The risk of bleeding was significantly reduced in subgroup analyses of apixaban compared with VKA [ARD: -3.9% (-7.0% to -0.9%)] and rivaroxaban [ARD: -5.6% (-9.5% to -1.7%)]. CONCLUSION : In this nationwide cohort study, there were no significant differences in the risks of all-cause mortality, stroke, and bleeding in patients with AF and VHD treated with VKA compared with FXa-I.