To evaluate changes in metabolic heterogeneity in rat liver lobules after partial hepatectomy, we measured parameters of carbohydrate and lipid metabolism cytophotometrically in periportal and pericentral zones of livers of mature female and male rats. Glycogen content was shown to be always higher in pericentral zones than in periportal zones. After a rapid depletion of glycogen stores during the first 8 hr after partial hepatectomy, the levels were restored to normal after 24 hr, but a significant depletion was found again at 48 hr after operation. These fluctuations were similar in female and male rat livers. The lipid content in control rat livers was low and was mainly localized in periportal zones. Partial hepatectomy caused a significant increase in lipid content after 24 to 48 hr in periportal zones only, which was distinctly higher in female than in male rat livers. Activity of NADPH-producing glucose-6-phosphate dehydrogenase was heterogeneously distributed in lobules of female control rats with highest activity in pericentral zones, whereas a lower but evenly distributed activity was found in lobules of control male rats. The activity was not affected by partial hepatectomy in male rats, whereas the activity in female rat livers decreased to levels found in male rats at 24 to 48 hr after operation. Another NADPH-producing enzyme, malate dehydrogenase, showed the highest activity pericentrally in female rats, and a low activity was evenly distributed in male rats. The activity did not change significantly after partial hepatectomy. The ketogenic enzyme β-hydroxybutyrate dehydrogenase showed the highest activity in pericentral zones of control livers. The activity in male rat livers was almost twice as high as in female rat livers in both zones. Partial hepatectomy caused a distinct reduction in activity in both zones and both sexes, but the strongest reduction was found periportally. Alkaline phosphatase activity, which is linked with bile acid secretion by hepatocytes, was low in control male and female rats and was mainly found periportally. The activity was increased dramatically at 24 to 48 hr after partial hepatectomy in both zones and particularly in male rat livers. The index for the Krebs cycle, succinate dehydrogenase activity, was highest in periportal zones. At 24 to 48 hr after partial hepatectomy, this preferential zonation was lost, and the activity was slightly higher in pericentral zones. This reversal of zonation was found in all livers of female and male rats investigated. Because the metabolic changes after partial hepatectomy cannot be explained by hormonal changes that are known to occur after partial hepatectomy, we concluded that the metabolic zonation in rat liver lobules is dynamic, sex dependent and adaptive. (HEPATOLOGY 1994;20:714–724).