Objective: This study is therefore designed to observe quantitative electron microscopic changes in living liver after the therapeutic, double therapeutic and three times the therapeutic dose of Diclofenac sodium. Study Design: It was an experimental study. Introduction: Acute liver failure due to drug toxicity accounts 50% cases of hepatotoxicity. Most of these drug induced failures are either metabolic or idiosyncratic. As liver is the primary organ for drug metabolism the danger of toxicity is always present. Most of the NSAID cause liver injury to some extent which is usually dose dependant as in acetaminophen and usually reversible when the drug is withdrawn. Diclofenac sodium the commonly used NSAID sometimes causes severe liver injury and the injury is clinically when the patient has developed symptoms and signs. There are very few studies in which dose dependant alterations at sub-cellular level are studied Methods: For this experimental study 88 male healthy rabbits were selected at IBMS of DUHS. The study period was from March to September 2009. The animals were divided into four groups each comprising of 22 animals. Group A served as control received normal saline 2 ml intraperitoneally, group B received diclofenac sodium 2mg/ kg, group C received 4mg/kg and group D received 6mg/kg all intraperitoneally for two weeks. At the end of this experiment the animals were sacrificed, liver dissected out, cut into pieces fixed in 4% gluteraldehyde and then processed for electron microscopy. Results: The changes in mitochondria were observed under E/M in different groups. It was found that the double and triple therapeutic doses produce significant changes in mitochondria in the form of swelling with damage to outer mitochondrial membrane, loss of cristae and appearance of densities. So it is suggested that this drug should be used with caution within therapeutic limits because it produces alterations in the sub-cellular structure even in non-toxic doses. Conclusion: Diclofenac sodium damages the mitochondria of hepatocytes in therapeutic as well as slightly higher than therapeutic dose. So we should make the public aware of hazards of increasing use of this drug for minor musculoskeletal disorders.