Background: Atrial fibrillation (AF) is quite prevalent in patient with chronic kidney disease (CKD). This study mainly investigated the net clinical benefit (NCB) property of non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with AF and CKD by a pooled-analysis. Methods: A comprehensive search of Medline, Embase, Cochrane Library and Clinical Trials.gov Website was performed for eligible randomized controlled trials (RCTs) reporting the efficacy and safety outcomes according to renal function of NOACs. Pre-specified outcomes and their number of patients needed to treat (NNT), including stroke/systemic embolism (SSE), major bleeding, and all-cause death, were evaluated using a random-effects model. NCB that balanced SSE and major bleeding was calculated using Singer's method. Results: Four phase III clinical trials including 70,952 patients were enrolled, 45,265 (64%) with CKD, and 25,687 (36%) without CKD; 41,942 (59%) taking NOACs and 29,010 (41%) taking warfarin. Risks of SSE [relative risk (RR): 0.80, 95% confidence interval (CI): 0.73-0.88, P<0.01], major bleeding (RR: 0.79, 95% CI: 0.66-0.96, P=0.017), and all-cause death (RR: 0.91, 95% CI: 0.84-0.99, P=0.031) were significantly lower in CKD patients with NOACs than those with warfarin, accompanying with a high absolute risk reduction (NNT: 182 for SSE; 122 for major bleeding; 196 for all-cause death). While NOACs were not superior to warfarin on SSE, major bleeding, and all-cause death in patients without CKD, the NCB of NOACs versus warfarin was progressively increased with the deterioration of renal function (NCB: 0.72 for no CKD, 1.59 for mild CKD, 2.74 for moderate CKD). Sensitivity analyses did not significantly affect the primacy results. Conclusions: NOACs, compared with warfarin, provide a better clinical profile on SSE, major bleeding, all-cause death, and NCB in CKD patients.