Recent reports indicate that transforming growth factor alpha (TGF-alpha) is produced within the liver and acts as the natural ligand of the epidermal growth factor (EGF) receptor causing the EGF receptor down regulation and the hepatocyte proliferation observed after partial hepatectomy. The reported phenomenon that an antibody to EGF inhibits the regenerative response to partial hepatectomy was therefore re-investigated. The IgG fraction of an anti-rat EGF antibody was injected intravenously at the time of partial hepatectomy, and its effects on regenerative DNA synthesis were compared with those of non-immune IgG. Injection of IgG reduced the DNA synthetic response to partial hepatectomy, assessed 24 hours after resection by 3H-thymidine incorporation, but the effects of normal and anti-EGF IgG were not statistically different, despite the presence of excess anti-EGF IgG in the circulation throughout the experimental period. However, anti-EGF IgG could completely block the proliferative response of hepatocytes in culture to EGF. These results support the suggestion that EGF is not the major mediator of hepatocyte DNA synthesis in the early stages of liver regeneration (less than 24 hours).