Omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to possess definitively suppressive effects on the growth of epithelial ovarian cancer cells. This study investigated the differential effects of pure EPA and DHA on the growth of epithelial ovarian cancer cells and the potential molecular mechanisms that may be involved. There were significant time- and dose-dependent inhibitory effects of both EPA and DHA on cellular proliferation of the epithelial ovarian cancer cell line TOV-21G (P < 0.05). TOV-21G cells pretreated with peroxisome proliferator receptor activator gamma (PPARγ) antagonist, GW9662, markedly suppressed EPA/DHA-induced apoptosis as determined by TUNEL assay, Annexin V-FITC/PI staining, and caspase-3 activity. EPA/DHA significantly induced PPARγ and p53 overexpression as observed in immunoblotting assay and the induction of p53 by EPA/DHA was abolished by GW9662. In all cases, the effect of DHA was significantly more potent than that of EPA (P < 0.05). Our findings suggested that DHA may be more effective than EPA in growth suppression of TOV-21G cells and the biologic effects may be partly mediated by PPARγ and p53 activation. Further research is required to elucidate additional divergent mechanisms to account for apparent differences between EPA and DHA.