Abstract Purpose Optimal resumption of oral anticoagulation therapy (OAC) after gastrointestinal bleeding (GIB)has not been well established. This study aimed to compare clinical outcomes between patients who resumed or discontinued OAC after index GIB. Methods We retrospectively enrolled consecutive patients with non-valvular atrial fibrillation (NVAF) and prior GIB from January 2018 to July 2022 in 16 public hospitals in Hong Kong. Resumption of OAC was substantiated by new prescription after index GIB on electronic medical records. Patients were divided into 5 groups: (i) OAC naïve (as reference group); (ii) resume direct oral anticoagulant (DOAC); (iii) resume Vitamin K antagonist (VKA); (iv) discontinue DOAC; (v) discontinue VKA. Endpoints included recurrent GIB, ischemic stroke and all-cause death. Risks of target events were estimated for all groups and compared with individuals without OAC, using adjusted sub-distribution hazard ratios (aSHR) derived from Fine and Gray regression models, accounting for death as competing risk for recurrent GIB and stroke, and COX proportional regression for all-cause mortality, adjusting for components of CHA2DS2VASC, HASBLED scores, causes of index GIB (i.e., GI ulcer, diverticular disease, angiodysplasia or undermined) and endoscopy intervention. Among patients who resumed OAC, outcomes were compared between different DOAC agents (i.e, apixaban, dabigatran, edoxaban, rivaroxaban), using VKA as reference. Results Of 2,350 patients identified (mean age 80.5±10.4, female 54.5%), 44.0% (n=1,034) were OAC naïve, 4.4% (n=103) discontinued VKA, 11.7% (n=275) discontinued DOAC, 11.2% (n=263) resumed VKA, and 28.7% (n=675) resumed DOAC. During a median follow-up duration of 1.2(IQR:0.2-2.5) years, discontinuation of DOAC (aSHR=0.5(0.29-0.9) was associated with lower risk of recurrent GIB, whereas resumption of VKA (aSHR=1.8(1.0-3.1)) was associated with the highest risk of recurrent GIB (Figure 1a). Among DOACs, apixaban (aSHR=0.5(0.3-0.9)) was associated with the lowest risk of recurrent GIB (Figure 1b). Risk of ischemic stroke across groups were similar. Patients who discontinued DOAC (aHR=1.4(1.2-1.6)) were at higher risk of all-cause mortality, whereas resumption of VKA (aHR=0.4(0.3-0.6)) and DOAC (aHR=0.4(0.4-0.5)) were both associated with decreased mortality (Figure 1c). Conclusion In this real-world dataset, resumption of VKA in NVAF patients after GIB was associated with high risk of recurrent GIB and lowest risk with apixaban. OAC resumption either VKA or DOAC was associated with reduced mortality.