Introduction Atrial fibrillation (AF) is an independent risk factor for end-stage renal disease (ESRD) among persons with chronic kidney disease (CKD), however, the association between AF and incident ESRD has not been examined in the general United States population. Methods A total of 24,953 participants (mean age 65 ± 9.0 years; 54% women; 40% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. AF was identified at baseline (2003-2007) from electrocardiogram data and self-reported history. Incident cases of ESRD were identified through linkage with the United States Renal Data System. Cox proportional-hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between AF and incident ESRD. Results A total of 2,155 (8.6%) participants had AF at baseline. Over a median follow-up of 7.4 years, 295 (1.2%) persons developed ESRD. In a model adjusted for demographics and potential confounders, AF was associated with an increased risk of incident ESRD (HR = 1.51, 95% CI = 1.08, 2.11). The association between AF and ESRD became non-significant after further adjustment for CKD markers (eGFR < 60 mL/min/1.73 m2 and urine albumin-to-creatinine ratio ≥ 30 mg/dL) (HR = 1.24, 95% CI = 0.89, 1.73). Conclusion AF is associated with an increased risk of ESRD in the general United States population and this association potentially is explained by underlying CKD.