We investigated whether melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cell lines such as SKOV3 and PA-1. To determine the anti-cancer effect of melittin on the ovarian cancer cell lines, apoptosis is analyzed by tunnel assay and apoptotic gene expression. Data were assessed by one-way analysis of variance (ANOVA). Melittin (0.5-2 μg/ml) supressed the growth of SKOV3 and PA-1 ovarian cancer cell lines by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptosis, expression of death receptor (DR) 3 and DR6 was increased in both cancer cell lines, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by melittin in SKOV3 and PA-1 ovarian cancer cell lines. These results suggest that melittin induces apoptotic cell death in ovarian cancer cell lines through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway.