The aim of this article is to elucidate the mechanism by which eicosapentaenoic acid (EPA) acts against cyclophosphamide (CP)-induced effects. The prevalence of micronuclei, the extent of lipid peroxidation, and the status of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) in both liver and serum of mice were used as intermediate biomarkers of chemoprotection. Lipid peroxidation and associated compromised antioxidant defenses (CAT and GPX) in CP treated mice were observed in the liver, serum, and were accompanied by increased prevalence of micronuclei in bone marrow. The number of MN was significantly different (p < 0.01) between the groups treated with CP (group III, IV, V, VI) and the solvent control (group II) (3.2 ± 0.7‰). There was a dose-dependent reduction in formation CP induced micronuclei by treatment with 100, 200, or 300 mg EPA/kg BW mice. Activities of SOD, CAT, and extent of lipid peroxidation were statistically different in liver cells of mice exposed to EPA only with CP compared with the CP group (group III). The present findings imply that EPA may be a potential antigenotoxic, antioxidant and chemopreventive agent and could be used as an adjuvant in chemotherapeutic applications. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2011.