© 2019 National Kidney Foundation, Inc. Rationale & Objective: Risk factors for kidney failure are the basis of live kidney donor candidate evaluation. We quantified risk for end-stage kidney disease (ESKD) by the biological relationship of the donor to the recipient, a risk factor that is not addressed by current clinical practice guidelines. Study Design: Retrospective cohort study. Setting & Participants: A cohort of 143,750 US kidney donors between 1987 and 2017. Exposure: Biological relationship of donor and recipient. Outcome: ESKD. Donors’ records were linked to national dialysis and transplantation registries to ascertain development of the outcome. Analytic Approach: Donors were observed over a median of 12 (interquartile range, 6-18; maximum, 30) years. Survival analysis methods that account for the competing risk for death were used. Results: Risk for ESKD varied by orders of magnitude across donor-recipient relationship categories. For Asian donors, risks compared with unrelated donors were 259.4-fold greater for identical twins (95% CI, 19.5-3445.6), 4.7-fold greater for full siblings (95% CI, 0.5-41.0), 3.5-fold greater for offspring (95% CI, 0.6-39.5), 1.0 for parents, and 1.0 for half-sibling or other biological relatives. For black donors, risks were 22.5-fold greater for identical twin donors (95% CI, 4.7-107.0), 4.1-fold for full siblings (95% CI, 2.1-7.8), 2.7-fold for offspring (95% CI, 1.4-5.4), 3.1-fold for parents (95% CI, 1.4-6.8), and 1.3-fold for half-sibling or other biological relatives (95% CI, 0.5-3.3). For white donors, risks were 3.5-fold greater for identical twin donors (95% CI, 0.5-25.3), 2.0-fold for full siblings (95% CI, 1.4-2.8), 1.4-fold for offspring (95% CI, 0.9-2.3), 2.9-fold for parents (95% CI, 2.0-4.1), and 0.8-fold for half-sibling or other biological relatives (95% CI, 0.3-1.6). Limitations: Insufficient sample size in some race and relationship groups. Absence of data for family history of kidney disease for donors biologically unrelated to their recipients. Conclusions: Marked differences in risk for ESKD across types of donor-recipient relationship were observed for Asian, black, and white donors. These findings warrant further validation with more robust data to better inform clinical practice guidelines.