Liver disease in humans and partial hepatic resection in animals are associated with decreased circulating somatomedin activity, suggesting that the liver may be an important site of somatomedin regulation. However, in both circumstances, concomitant alterations in nutrition could contribute to changes in somatomedin activity. To distinguish the consequences of reduced liver mass from those of decreased food intake, we examined the effects of partial hepatic resection in rats with controlled nutrition. Animals were first subjected to 65% partial hepatectomy, and fed ad libitum. At death, circulating somatomedin activity was measured in a bioassay using costal cartilage from hypophysectomized rats. After partial hepatectomy, somatomedin activity was decreased for 2 days, then rose toward normal. Somatomedin activity returned to control levels by 6 days after partial hepatectomy. Food intake also decreased (11 g/100 g over 48 h vs. 24 g in controls; P less than 0.001), and animal weight remained below control levels for 10 days (P less than 0.001) despite full liver regeneration. To control for the effects of nutrition, we then provided partially hepatectomized and sham-operated animals with equicaloric restricted diets (approximately 80% of ad libitum diet) based on spontaneous food intake after partial hepatectomy. With this paradigm, both groups exhibited a transient decrease in somatomedin activity. However, despite equal food intake, partially hepatectomized animals had higher somatomedin activity than sham-operated controls over a 7-day period (P less than 0.03, by analysis of variance). Differences were greatest after 72 h, when regeneration was 80% complete (somatomedin activity, 79% of normal after partial hepatectomy vs. 63% after sham procedures; P less than 0.02). In hypophysectomized rats, liver regeneration was retarded (29% at 72 h), and serum somatomedin activity remained at posthypophysectomy levels. We conclude that when rats are provided equicaloric restricted diets, somatomedin activity is higher after partial hepatectomy than after sham operation. Under these conditions, the regenerating liver may produce more somatomedins and/or less somatomedin inhibitors. Pituitary factors may be important in the regenerative response to partial hepatic resection in the rat.