BACKGROUND: Whether direct oral anticoagulants (DOACs) are a safe and effective alternative to warfarin in patients with atrial fibrillation and mitral stenosis (AF-MS) remains controversial. OBJECTIVE: To evaluate the effectiveness and safety of DOACs versus warfarin in patients with AF-MS. DESIGN: Observational cohort study using target trial emulation. SETTING: Population-wide insurance claims data in Taiwan. PARTICIPANTS: Patients diagnosed with AF-MS and prescribed either DOACs or warfarin between 1 January 2011 and 31 December 2021 were included in the study. INTERVENTION: DOACs or warfarin. MEASUREMENTS: Absolute risk differences (RDs) and risk ratios (RRs) at 1 year and 5 years of follow-up for ischemic stroke, systemic embolism, composite stroke, myocardial infarction (MI), intracranial hemorrhage, gastrointestinal bleeding, bleeding at other critical sites, and all-cause death. RESULTS: Compared with warfarin, DOACs were associated with an increased risk for ischemic stroke (RD, 4.97 percentage points [95% CI, 1.27 to 8.57 percentage points]; RR, 1.22 [CI, 1.05 to 1.41]) and composite stroke (RD, 5.56 percentage points [CI, 1.77 to 8.97 percentage points]; RR, 1.23 [CI, 1.07 to 1.42]) and a decreased risk for MI (RD, -1.61 percentage points [CI, -3.17 to -0.03 percentage points]; RR, 0.61 [CI, 0.37 to 0.99]) at the 1-year follow-up. Rivaroxaban increased the risk for ischemic stroke during both short- and long-term follow-up periods. The 2 groups did not differ in risks for bleeding or all-cause death. LIMITATION: Limited sample size, lack of detailed information on MS severity, and lack of international normalized ratio measurements. CONCLUSION: In Asian patients with AF-MS, DOACs were associated with an increased 1-year risk for stroke but a decreased risk for MI compared with warfarin. PRIMARY FUNDING SOURCE: Research Grants Council of Hong Kong.