Background: Edoxaban (edox), an oral factor Xa inhibitor with 50% renal clearance, was non-inferior to warfarin for prevention of thromboembolic events and significantly reduced bleeding in pts with AF. However, a detailed analysis of the impact of creatinine clearance (CrCl) on clinical outcomes with edox has not been described. Purpose: We evaluated the safety, efficacy and net clinical outcome of edox vs warfarin (warf) across the range of baseline CrCl in the ENGAGE AF-TIMI 48 trial. Methods: 14,071 AF pts at moderate-to-high risk of stroke were randomized to edox 60mg QD or warf. Severe renal dysfunction (CrCl<30ml/min) was exclusionary and a CrCl 30-50 resulted in a 50% dose reduction of edox (30mg QD). Endpoints of stroke or systemic embolism (SSE), ISTH major bleeding (MB) and the primary net clinical outcome of SSE/MB and all-cause mortality (ACM) were evaluated by intention-to-treat analysis by the pre-specified singular CrCl cutpoint of 50ml/min and additional exploratory cutpoints. Results: The relative risk of SSE with edox vs warf in the pre-specified analysis in those with CrCl≤50 (HR 0.87, 0.65-1.18) was similar to those with CrCl>50 (HR 0.87, 0.72-1.04; p-int=0.94). Evaluation by more granular, exploratory cutpoints demonstrated higher rates of SSE (Fig 1a; p-int<0.001) and ischemic stroke (p-int=0.05) with edox vs warf in the upper range of CrCl, but lower rates of bleeding were observed at all levels of CrCl with edox (Fig 1a; p-int=0.39). For the net clinical outcome (SSE/MB/ACM), there was no significant difference between edox and warf at higher levels of renal function due to the preserved effect on bleeding and mortality (Fig 1b; p-int 0.17). An on-treatment analysis with plasma drug levels will be shown. Conclusion: While there is a trend towards decreasing efficacy with increasing CrCl for edox compared to well-managed warfarin, the overall safety and net clinical benefit of edox compared to warfarin is consistent across renal function groups.