The role of protein and energy malnutrition in the pathogenesis of isoniazid (INH)-rifampicin (RMP) induced hepatic injury was investigated. Status of oxidative/antioxidative profile was the mechanistic approach to enumerate the nature of injury. Weanling rats were fed with ad-libitum quantity of isocaloric diets containing 5% casein based proteins for the production protein and energy malnutrition. INH and RMP (50 mg/kg of each) were injected intraperitonially for a period of two weeks. Analysis of serum transaminases and histopathological observations revealed hepatic injury. Hepatic thiols and blood glutathione were decreased significantly in INH and RMP treated groups. Among antioxidative enzymes, hepatic superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferases (against CDNB and DCNB substrates) showed significant decline of activities in INH and RMP treated groups. The activities of hepatic glutathione reductase, glutathione-S-transferase (against EA substrate) and lipid peroxidation observed significant elevation. A careful comparison of protein and energy restriction revealed a greater degree of oxidative-stress of INH-RMP in protein-restriction.