The hypothesis that breast-feeding can provide protection against the development of insulin-dependent diabetes mellitus (IDDM) and would, therefore, be less common among subjects with IDDM was tested with a retrospective design. Cases (n = 268) were selected from the Colorado IDDM Registry and the Barbara Davis Center for Childhood Diabetes (Denver, CO). Two control groups were recruited, one from physicians' practices throughout Colorado (n = 291) and the second through random-digit dialing from the Denver area (n = 188). Cases were less likely to have been breast-fed than controls after adjustment for birth year, maternal age, maternal education, family income, race, and sex [adjusted odds ratio (OR) = 0.70; 95% confidence interval (CI) = 0.50-0.97]. This finding was consistent for both control groups and by birth-year intervals. A greater decrease in risk of IDDM was seen among subjects who had been breast-fed to an older age (for breast-feeding duration of greater than or equal to 12 mo, adjusted OR = 0.54, 95% CI = 0.27-1.08). The amount of IDDM that might be explained by breast-feeding habits (population percentage attributable risk) ranged from 2 to 26%, varying according to the breast-feeding prevalence reported in other studies. Replication of this work in different populations, controlled for the strong secular trends in breast-feeding habits, is critical before the hypothesis of protection is accepted.