Background: Birth weight (BW) and family history (FH) of end-stage renal disease (ESRD) have been shown to have an independent association with development of subsequent ESRD. This study was undertaken to determine the effects of BW (low BW suggesting a congenital reduction in functional nephron number) on the observed familial aggregation of ESRD. Methods: Cases were identified from the ESRD Network 6 ‘Family History of ESRD’ Study and BW was determined from birth certificate records maintained at the Office of Vital Records, South Carolina Department of Health and Environmental Control. BW and FH of ESRD data were available in 387 patients who initiated dialysis therapy between 1993 and 1997. Multiple logistic regression analysis was performed to assess the risk of low BW (<2,500 g) and high BW (≧4,000 g) on FH of ESRD. Results: A FH of ESRD in first or second-degree relatives was present in 24% of cases. No significant differences were observed in the frequency of a positive FH of ESRD in those with low BW compared to those with normal BW. There was a significant reduction in the prevalence of a FH of ESRD in those with high BW, compared to those with a normal BW (risk ratio 0.32, CI 0.11–0.94). Conclusion: The clustering of either high BW or low BW within multiply affected ESRD families does not account for the observed familial aggregation of ESRD. In addition, high BW was associated with a reduced familial aggregation of ESRD.