Hepatic expression of the protooncogenes c‐fos and c‐myc occurs within 2 h after partial hepatectomy, and these immediate early genes are thought to prime the hepatocytes for subsequent proliferation. To examine whether such gene activation occured in the setting of hepatocyte proliferation after toxic liver injury, protooncogene expression was examined during the regenerative response following liver injury from carbon tetrachloride (CCI₄) or galactosamine (GaIN). The pattern of protooncogene expression after CCI₄ mirrored that seen after partial hepatectomy, with rises in c‐fos and c‐myc mRNA content within 2 h, and then a rapid return to baseline levels. In contrast, early c‐fos and c‐myc expression did not occur after GaIN injury. Instead GaIN‐induced regeneration led to a delayed and prolonged c‐fos an c‐myc activation which peaked 24–48 h after injury. Increase in c‐jun, jun‐B, and jun‐D mRNA levels also occured in both models at times similar to the rises of c‐fos and c‐myc expression. Although the timing of DNA synthesis was identical after GaIN or CCI₄ treatment the proliferative response after GaIN injury was significantly less than that of CCI₄, and marked by the histologic appearance of oval cells. The coadministration of 2‐acetylaminofluorene, an inhibitor of differentiated hepatocyte proliferation, together with CCI₄ altered the usual pattern of post‐CCI₄ protooncogene expression to one resembling that seen after GaIN injury. Thus, the timing of protooncogene expression during liver regeneration may vary considerably. These variations may influence the nature of the proliferative response in terms of which cell types(s) proliferates, and the amount of regeneration that ensures. © 1993 Wiley‐Liss, Inc.