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Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This research was supported by a grant from the Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC21C0028). Background In patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), gastrointestinal bleeding (GIB) is itself a serious event for the patient, and it causes an increase in the thromboembolic risk caused by discontinuation of anticoagulation therapy. There are limited data on the benefit of preventive PPI use to reduce the risk of GIB in DOAC users. Methods We included patients with AF receiving DOAC from 2013 to 2020 based on the Korean Health Insurance Review and Assessment database. For comparison between patients with and without PPI, propensity score (PS) weighting method was used. Primary outcome was major GIB and secondary outcomes were major upper GIB and upper GIB requiring transfusion. Results A total of 171,494 patients were included (mean 72±10 years, mean CHA2DS2-VASc 4.3±1.8; 50,577 of rivaroxaban, 23,010 of dabigatran, 54,461 of apixaban, and 43,446 of edoxaban). Among the total population, 40% of patients were prescribed PPI and 55% of PPI users were prescribed low dose PPI. After PS weighting, patients with PPI were associated with lower risks of major GIB, major upper GIB, and upper GIB requiring transfusion than those without PPI (hazard ratio [95% confidence interval]; 0.816 [0.758-0.878], 0.834 [0.770-0.901], and 0.814 [0.734-0.902], respectively, Figure A). Patients with low dose PPI showed significant risk reduction for major GIB, major upper GIB, and upper GIB requiring transfusion than those without PPI (0.570 [0.515-0.632], 0.563 [0.505-0.628], and 0.505 [0.435-0.587], respectively). The protective effect of PPI was slightly different among DOAC types (Figure B). In the subgroup analyses, major GIB risk reduction of PPI co-therapy was more accentuated in patients older than 75 years and those with underlying GI disease or symptoms. Conclusion In this largest Asian cohort of patients with AF receiving DOAC, PPI co-therapy might be beneficial to reduce the risk of major GIB and upper GIB. This was consistently observed with low-dose PPI. The protective effect of PPI was more pronounced in the high bleeding risk patients.