Familial aggregation of end-stage renal disease (ESRD) is frequently observed in the common causes of kidney failure. It is unknown whether the clinical course of nephropathy differs based on an individual's family history of ESRD. The ESRD Network 6 Family History of ESRD database was analyzed to compare dialytic survival among patients with first- or second-degree relatives on dialysis therapy (positive family history) with those lacking relatives with ESRD (negative family history). Study participants included 3,442 adult, black or white, incident patients with ESRD who initiated dialysis therapy in ESRD Network 6 facilities in 1995 and participated in the Network-sponsored Family History of ESRD study. All deaths were reported to the Network and used to calculate mortality rates. The relative risk for death was used to compare rates between levels of patient characteristics. Multivariate analyses used proportional hazards regression. Overall, 730 patients (21.2%) had a positive family history of ESRD. Black patients, those who were younger at the onset of ESRD, patients with greater degrees of functional status, and women were more likely to have a positive family history. During 9,000 patient-years of follow-up, 1,599 patients died (17.8 deaths/100 dialysis-years). Univariate analyses showed that patients with a positive family history of ESRD had 20% lower mortality than those with a negative family history of ESRD (relative risk, 0.80; 95% confidence interval, 0.7 to 0.9; P = 0.001). Older age, white race, diabetic nephropathy, lower functional status, lower serum albumin level, congestive heart failure, and ischemic heart disease also were associated with greater mortality rates. Multivariate analyses showed that only older age at onset of ESRD, white race, low functional status, ESRD caused by diabetes, and congestive heart failure were associated with increased mortality. A family history of ESRD in either first- or second-degree relatives was no longer a significant determinant of survival. We conclude that familial clustering of ESRD does not significantly impact on dialytic survival after controlling for the competing effects of patient race, age of ESRD onset, and the presence of diabetes mellitus. © 2001 by the National Kidney Foundation, Inc.