The association between the diabetic intrauterine environment and renal disease was examined cross-sectionally in 503 Pima Indians with type 2 diabetes. Subjects were selected from participants in an ongoing study of diabetes and its complications in the Gila River Indian Community of Arizona. Subjects' exposure to diabetes in utero was established from periodic examinations conducted as part of the study. The prevalence of elevated urinary albumin excretion (UAE) (albumin-to-creatinine ratio > or = 30 mg/g) was 40% (83 of 207) in the offspring of nondiabetic mothers, 43% (105 of 246) in the offspring of prediabetic mothers (i.e., women who were not diabetic at the time of the pregnancy but who developed diabetes after the pregnancy), and 58% (29 of 50) in the offspring of mothers who had diabetes during pregnancy. After controlling for age, sex, duration of diabetes, HbA1c, and mean arterial pressure in the offspring in a logistic regression analysis using generalized estimating equations, maternal diabetes during pregnancy was strongly associated with elevated UAE. The odds of elevated UAE in the offspring of mothers who had diabetes during pregnancy was 3.8 times (95% CI 1.7-8.4) that of the offspring of prediabetic mothers; the odds of elevated UAE in the offspring of nondiabetic and prediabetic mothers were similar (odds ratio of 0.94; 95% CI 0.59-1.5). We concluded that exposure to a diabetic intrauterine environment increases the risk of elevated UAE in diabetic Pima Indians. The effect of this exposure appears to be independent of other susceptibility factors that lead to nephropathy in diabetes.