Methotrexate (MTX) is widely used in the therapy of various types of malignancy. The present work was designed to investigate the histological and histochemical changes in the liver of albino rat following methotrexate administration. Fifteen adult male albino rats were used in the present work. They were divided into three main groups: Group I was kept without treatment and served as control. Groups II and III were given intraperitoneal injections of normal saline and MTX, respectively, at a dosage of (0.5 mg/Kg) twice weekly for total durations of 3, 6 and 9 weeks. The rats were sacrificed and the livers were excised and processed for histological and histochemical study. Examination of sections of the livers of group III showed mononuclear cell infiltration and an increase in the amount of collagen fibers in the portal tracts. There were focal areas of liver cell necrosis with distortion of the normal hepatic architecture. Moreover, there was a gradual and progressive decrease of glycogen content in the hepatocytes. Furthermore, succinic dehydrogenase and alkaline phosphatase activity were also decreased. In addition there was an increase in acid phosphatase activities in the degenerated areas and loss of activities in areas of massive cellular necrosis. It was concluded that repeated injections of MTX causes hepatic damage of a definite magnitude. This hepatotoxicity progressed with increasing cumulative doses of methotrexate. The present study provided further evidence to the cytotoxic potency of this antifolate