Insulin-dependent diabetes mellitus in both humans and animals leads to structural and functional changes including hepatomegaly. This study examined hypertrophy, hyperplasia, and apoptosis, three basic aspects of tissue growth, in livers of Sprague-Dawley and Wistar rats made diabetic by iv injection of streptozotocin 8, 30, or 90 days previously. Immunohistochemical measurement of proliferating cell nuclear antigen revealed that hepatic DNA labeling indices were similar in normal control animals and diabetic rats 30 or 90 days post diabetic induction, but were reduced to 45 to 50% of control in insulin-treated diabetic animals, perhaps due to altered receptor activity or to partial insulin resistance, as reported previously. Flow cytometry indicated a 613% increase in diploid hepatocytes in the livers of diabetic rats 30 days after the onset of diabetes, compared to control. Diabetic livers contained 29% fewer tetraploid cells, 81% fewer octaploid cells, and 20% more binucleated hepatocytes than normal controls. At 90 days, the overall smaller size of hepatocytes in diabetic tissue was evidenced by more cells per area. Insulin treatment prevented some of these changes, but did not restore ploidy to a normal distribution. Mitosis, while 300% of normal at 8 days after streptozotocin injection, was reduced to 25% of normal after 90 days of diabetes. The morphological evidence of apoptosis was decreased by 23% to 76% in the diabetic liver, and was reversed but not normalized by insulin treatment. This study indicates that the hepatomegaly observed in streptozotocin-induced experimental diabetes may be due primarily to early hyperplasia, and later decreased apoptosis.