There is strong evidence for clustering of renal disease in type 1 diabetes, but few data exist with respect to type 2 diabetes. The objective of this case-control study is to determine whether there is a familial predisposition to the development of proteinuria in patients with type 2 diabetes. Fifty patients with type 2 diabetes with macroproteinuria (protein > or = 500 mg/24 h) with no evidence of causes other than diabetic nephropathy on investigation were identified through routine screening. These patients had 25 living sibs with diabetes, of whom 24 sibs agreed to participate on the study. For each of these sibs, two controls with non-insulin-dependent diabetes were randomly selected, individually matched for age, sex, and duration of diabetes. Twelve of 24 sibs (50%) and 9 of 48 controls (18.8%) had proteinuria (P < 0.01). Systolic and diastolic blood pressure and the proportion on antihypertensive treatment were similar in the two groups. Our data suggest there is increased prevalence of macroproteinuria in diabetic sibs of macroproteinuric patients with type 2 diabetes in a population of white, Caucasian, European descent.