Using a case-control study design, we examined the hypothesis that early exposure to cow's milk and solid foods increased the risk of IDDM. An infant diet history was collected from 164 IDDM subjects from the Colorado IDDM Registry with a mean birth year of 1973, and 145 nondiabetic population control subjects who were frequency matched to diabetic subjects on age, sex, and ethnicity. Early exposure was defined as exposure occurring before 3 mo of age. After controlling for ethnicity, birth order, and family income, more diabetic subjects were exposed early to cow's milk (OR 4.5, 95% CI 0.9-21.4) and solid foods (OR 2.5, CI 1.4-4.3) than control subjects. To examine this association while accounting for the genetic susceptibility to IDDM, we defined individuals as high and low risk by an HLA-DQB1 molecular marker. Early exposure to cow's milk was not associated with elevated risk for IDDM in low-risk individuals. Relative to unexposed low-risk individuals, early exposure to cow's milk was strongly associated in individuals with a high risK marker (OR 11.3, CI 1.2-102.0). Similar findings were observed for early exposure to solid foods. These data indicate that early exposure to cow's milk and solid foods may be associated with increased risk of IDDM. The inclusion of HLA-encoded risk in the analyses demonstrates the combined effect of genetic and environmental factors.