AIMS: This study, using a prospective cohort, evaluated the effectiveness and safety of off-label reduced-dose apixaban versus the on-label dose in atrial fibrillation (AF) patients meeting a single dose reduction criterion. METHODS AND RESULTS: The efficAcy and Safety of aPixaban In Real-world practice in Korean frail patients with AF (ASPIRE) study is a multicenter, prospective observational cohort involving AF patients who met a single dose reduction criterion of apixaban. Patients were divided into two groups: on-label standard dose (5 mg twice daily) and off-label reduced dose (2.5 mg twice daily). The primary effectiveness outcome was stroke/systemic embolism (SSE), and the primary safety outcome was major bleeding. Of 1 944 patients (mean age 74.3 ± 7.9 years, 56% women), 997 (51%) were receiving off-label reduced dose apixaban. The off-label reduced dose group was older, had more comorbidities, higher concomitant antiplatelet use, and higher CHA2DS2-VASc and HAS-BLED scores. During follow-up (1.0 ± 0.2 year), crude incidence rates were 0.9 vs. 0.7 per 100 person-years for SSE and 0.5 vs. 1.0 for major bleeding in the on-label vs. off-label groups. After inverse probability of treatment weighting, the off-label reduced dose group showed no significant differences in the risk of SSE (HR 0.67, 95% CI 0.28-1.59, p = 0.370) and major bleeding (HR 1.38, 95% CI 0.44-4.35, p = 0.578) compared to the on-label standard dose group. CONCLUSION: In Korean patients with AF meeting a single dose reduction criterion of apixaban, off-label reduced-dose apixaban showed no significant differences in SSE and major bleeding compared to the on-label standard dose. These findings suggest that individualized anticoagulation strategies, such as reduced dose apixaban, may be beneficial for patients with a high risk of bleeding.