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Aim and Scope: It is becoming progressively more understandable that overdose of indomethacin in both humans and animals causes severe hepatotoxicity. The present study was conducted to determine the biochemical and histological changes in liver due to of indomethacin administration in adult male albino rats. Drug-treated rats were given food for the next 24 h until they were sacrificed. Measurement of gamma glutamylransferase (Ɣ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline phosphatase (ALP) and bilirubin, and 5-nucleotidase (5-NT) in serum were performed, and the histopathology of the liver in all groups were investigated. Statistical evaluation of the results at a p< 0.05 elucidated significantly elevated values of these enzymes when compared with control. Results: Indomethacin induced rats showed a significant increase in serum levels of AST and ALT, ALP, GGTP, 5-NTand 5-NT, whereas the serum total protein, albumin was significantly decreased in treated group compared with group 1. The histological examination shows, heavy lymphocytes infiltration, degenerative changes in the hepatocytes, dilated and congested portal vein. These findings support the need for caution in administration of indomethacin particularly for long term administration..