The contribution of albuminuria to the increased risk of incident end-stage renal disease (ESRD) in individuals with a family history of ESRD has not been well studied. Prospective cohort study. We analyzed data for family history of ESRD collected from 19,409 participants of the Renal REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study. Family history of ESRD was ascertained by asking "Has anyone in your immediate family ever been told that he or she had kidney failure? This would be someone who is on or had been on dialysis or someone who had a kidney transplant." Incidence rate for ESRD. Morning urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Incident cases of ESRD were identified through the US Renal Data System. A family history of ESRD was reported by 11.1% of participants. Mean eGFRs for those with and without a family history of ESRD were 87.5 ± 22.2 (SD) and 86.5 ± 19.3 mL/min/1.73 m 2, respectively (P = 0.05) and the respective geometric mean ACRs were 12.2 and 9.7 mg/g (P < 0.001). ESRD incidence rates for those with and without a family history of ESRD were 244.3 and 106.1/100,000 person-years, respectively. After adjusting for age, sex, and race, the ESRD HR for those with versus those without a family history of ESRD was 2.13 (95% CI, 1.18-3.83). Adjustment for comorbid conditions and socioeconomic status attenuated this association (HR, 1.82; 95% CI, 1.00-3.28), and further adjustment for baseline eGFR and ACR completely attenuated the association between family history of ESRD and incident ESRD (HR, 1.12; 95% CI, 0.69-1.80). The report of a family history of ESRD was not validated. Family history of ESRD is common in older Americans and the increased risk of ESRD associated with a family history reflects lower GFR, higher albuminuria, and comorbid conditions. © 2011 by the National Kidney Foundation, Inc.