The db/db mutant mouse is a rodent model of genetic diabetes that develops renal glomerular lesions with striking mesangial matrix accumulation by the age of 16 weeks, after 8-10 weeks of sustained hyperglycemia. However, abnormalities in renal function that antedate or accompany the appearance of these pathologic changes, which resemble those found in human diabetes, have not been delineated. We therefore examined renal function in young db/ db mice and their nondiabetic db/m littermates from the age of 8 through 15 weeks. Serum creatinine and blood urea nitrogen concentrations at the onset of diabetes in db/db mice did not differ significantly from mean concentrations in db/m controls. An elevated creatinine clearance, due in large part to increased body weight, and increased urinary albumin excretion were observed in db/db compared with db/m mice soon after establishment of sustained hyperglycemia. A relative reduction in creatinine clearance was demonstrable in db/db mice at the age of 15 weeks, coincident with the appearance of overt compromise in renal function manifested by frank increases in the serum creatinine and blood urea nitrogen. The findings indicate that the well-documented glomerular pathology in db/db mice is accompanied by definable alterations in renal function, which are similar in chronology and nature to those found in human diabetes.