BACKGROUND & AIMS: Direct oral anticoagulant (DOAC) agents increase the risk of gastrointestinal (GI) bleeding. We investigated which DOAC had the most favorable GI safety profile and compared differences among these drugs in agerelated risk of GI bleeding. METHODS: We conducted a retrospective, propensity-matched study using administrative claims data from the OptumLabs Data Warehouse of privately insured individuals and Medicare Advantage enrollees. We created 3 propensity-matched cohorts of patients with non-valvular atrial fibrillation with incident exposure to dabigatran, rivaroxaban, or apixaban from October 1, 2010 through February 28, 2015. We compared data on rivaroxaban vs dabigatran for 31,574 patients, data on apixaban vs dabigatran for 13,084 patients, and data on apixaban vs rivaroxaban for 13,130 patients. Cox proportional hazards models, stratified by age, were used to estimate rates of total GI bleeding. RESULTS: Baseline characteristics were well balanced among sub-cohorts. GI bleeding occurred more frequently in patients given rivaroxaban than dabigatran (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.00 +/- 1.45). Apixaban was associated with a lower risk of GI bleeding than dabigatran (HR, 0.39; 95% CI, 0.27 +/- 0.58; P <.001) or rivaroxaban (HR, 0.33; 95% CI, 0.22 +/- 0.49; P <.001). Rates of events for all DOACs increased among patients 75 years or older. Apixaban had a lower risk of association with GI bleeding in the very elderly than dabigatran (HR, 0.45; 95% CI, 0.29 +/- 0.71) or rivaroxaban (HR, 0.39; 95% CI, 0.25 +/- 0.61). Median times to GI bleeding were < 90 days for apixaban and rivaroxaban and < 120 days for dabigatran. CONCLUSIONS: In a population-based study of patients receiving DOAC agents, we found apixaban had the most favorable GI safety profile and rivaroxaban the least favorable profile. GI bleeding events among patient aged 75 years or older taking DOACs increased with age; the risk was greatest among persons 75 years. Apixaban had the most favorable GI safety profile among all age groups.