Background The association between waist circumference and end-stage renal disease (ESRD) remains poorly explored. Study Design Longitudinal population-based cohort. Setting & Participants Participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study (n = 30,239) with information for body mass index (BMI), waist circumference, spot urine albumin-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR; n = 26,960). Predictor Elevated waist circumference or BMI. Outcomes & Measurements Incident cases of ESRD were identified through linkage of REGARDS participants with the US Renal Data System. Results Mean baseline age was 64.8 years, 45.8% were men, and 40.3% were black. Overall, 297 (1.1%) individuals developed ESRD during a median of 6.3 years. After adjustment for all covariates including waist circumference, no significant association was noted between BMI categories and ESRD incidence compared to BMI of 18.5 to 24.9 kg/m2 (referent). Higher waist circumference categories showed significantly increased hazard rates of ESRD, with waist circumference ≥ 108 cm in women and ≥122 cm in men (highest category) showing a 3.97-fold higher hazard rate (95% CI, 2.10-6.86) for ESRD compared to waist circumference < 80 cm in women and <94 cm in men (referent) after adjusting for demographic factors and BMI. However, no significant association was noted between any waist circumference category and ESRD incidence after adjustment for obesity-associated comorbid conditions and baseline ACR and eGFR. Limitations Short follow-up period (6.3 years) to assess ESRD risk among adults with eGFRs > 60 mL/min/1.73 m2. Conclusions In this cohort of older adults, obesity as measured by waist circumference is associated with higher ESRD risk even with adjustment for BMI, whereas obesity as measured by BMI is not associated with higher ESRD risk after adjustment for waist circumference. However, no significant association is noted between increased waist circumference and ESRD risk after adjustment for obesity-related comorbid conditions, eGFR, and ACR.