The liver is thought to be the locus of nutritional/hormonal regulation of circulating insulin-like growth factor-I (IGF-I). To probe the basis of nutritional regulation, we examined changes in serum IGF-I, hepatic content of extractable IGF-I immunoreactivity (a high Mr putative precursor) and hepatic IGF-I mRNA during fasting and refeeding in rats. Preliminary studies revealed that the hepatic level of IGF-I mRNA was consistently reduced only after food was withheld for 3 days, so the effects of refeeding were subsequently examined in such animals. After 3 days of fasting, animals lost 30% of their initial weight; weight regain was apparent within 3 h of refeeding ad libitum and, after 48 h, weight was comparable to initial fed levels. Fasting reduced levels of serum and extractable hepatic IGF-I to 19 and 26% of control (fed) values respectively (both PPPPPP<0·002) between each pair of parameters. Since refeeding of fasted animals led to a rise in IGF-I mRNA which preceded rises in serum and hepatic IGF-I, our findings are consistent with the hypothesis that nutritional regulation of circulating IGF-I involves modulation at the level of hepatic IGF-I mRNA. The changes in the ratio of hepatic to serum IGF-I during fasting and refeeding indicate that there may also be regulation at the level of hepatic release.