The effect of the long-acting somatostatin analog octreotide on liver regeneration was studied in rats in vitro and in vivo. The effect of continuous subcutaneous octreotide infusion on regenerative liver weight and relative DNA synthesis was examined in rats that had undergone 70% hepatectomy. Administration of octreotide resulted in a 33% reduction of regenerating liver weight at 72 hours and a 67% reduction of regenerative hepatocellular hyperplasia at 24 hours. This effect was reversed within 12 hours after withdrawal of the drug. The mechanism for the inhibitory effect of octreotide appears to be indirect, because experiments in hepatocyte cultures did not demonstrate a direct inhibitory effect on serum-free or epidermal growth factor-induced regenerative hepatocyte proliferation. Because insulin levels were suppressed by octreotide in the in vivo experiments, suppression of hepatotrophs may be the mechanism by which octreotide inhibits liver regeneration.