The expression of the immediate early genes (IEGs) c-fos and e-jun have been hypothesized to potentially play key roles in mediating cellular responses following injury to the liver. In this study, we sought to evaluate the potential involvement of c-jun and c-fos as determinants either of cellular regeneration or programmed cell death following ischemia/reperfusion (I/R) in mouse liver. To this end, we have analyzed the in situ messenger RNA (mRNA) expression patterns of c-jun and c-fos following lobar I/R in mouse liver. The expression patterns of c-jun and c-fos were correlated with four criteria for tissue repair and injury, including: 1) morphological determinations of regeneration using immunocytochemical detection of proliferating cell nuclear antigen (PCNA), 2) programmed cell death (apoptosis) using the in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, 3) histopathologic assessment of hepatocellular necrosis, and 4) serum glutamic pyruvic transaminase (GPT) levels. Increasing lengths of lobar ischemia for 3, 60, and 90 minutes followed by reperfusion directly correlated with the extent of liver injury as determined by serum transaminases and hepatocellular necrosis. PCNA expression in the liver was elevated at 1 to 6 hours following liver reperfusion and returned to baseline levels by 20 hours in both ischemic and nonischemic lobes. In contrast, apoptotic responses peaked only in ischemic lobes at 6 hours′ postreperfusion and remained elevated out to 20 hours. Two distinct patterns of c-jun and c-fos expression were observed during the acute (1-3 hours) and subacute (6-20 hours) phases of liver responses to I/R including: 1) coexpression of c-jun and c-fos mRNA within damaged regions of the liver at 1 to 3 hours′ postreperfusion, and 2) a decline in c-fos expression with sustained high levels of c-jun expression within a subset of cells bordering necrotic/apoptotic regions of the liver at 6 to 20 hours′ postreperfusion. These findings suggest that coexpression of both c-jun and c-fos may be involved in mediating early tissue repair processes in liver remodeling following I/R. In contrast, the onset of hepatocellular apoptosis correlated with sustained c-jun expression, in the absence of c-fos, and suggests that these changes in the molecular profile of immediate early gene expression may regulate cellular responses that signal hepatocytes for programmed cell death.