Infusion of increasing concentrations (0.2-1 mM) of the quinone, menadione, caused step-wise increases in oxygen uptake in perfused livers from fasted rats presumably due to oxygen-dependent redox cycling. Maximal increases in oxygen uptake of about 40 mumol/g/h were observed with 0.8 to 1.0 mM menadione. This increase in oxygen uptake was confined to periportal areas of the liver lobule suggesting that redox cycling due to menadione occurs exclusively in cells localized around the portal triad. After 60 min of infusion of menadione (1 mM), lactate dehydrogenase was released from the liver at rates between 60 to 70 U/g/h. Under these conditions, trypan blue was taken up by virtually all hepatocytes in periportal regions of the liver lobule. In contrast, dye was not taken up by cells in pericentral areas. It is concluded that menadione is selectively toxic to hepatocytes located in oxygen-rich periportal regions of the liver lobule.