Objective. Utilizing ovarian cancer cell lines, we examined the effect of IFN-γ on each type of TNF receptor. Additionally, we sought to determine the effect of receptor modulation on TNF-α-mediated cytolysis. Methods. Ovarian cancer cell lines Caov-3, A2780, and SK-OV-3 were employed. The number of TNF receptors was determined by a TNF-α binding assay utilizing 125I-labeled TNF-α. Monoclonal antibodies specific for the 55- to 60-kDa (TR60) and the 75- to 80-kDa (TR80) TNF receptors were used to determine the relative density of each receptor type. Northern blot analyses were performed employing cDNA probes for the TR60 and TR80 mRNAs. To elucidate which receptor(s) was responsible for mediating the signal for cytolysis, 24-h MTT cytolytic assays were performed in the presence of receptor-specific monoclonal antibodies. Results. IFN-γ treatment resulted in an increase in TNF receptors in the cell lines A2780 and Caov-3 (P < 0.001), but not SK-OV- 3. Northern blot analyses suggested distinct regulatory mechanisms for the two receptors. In Caov-3 and SK-OV-3 cells a synergistic increase in TNF-α- mediated cytolysis was seen when cells were pretreated with IFN-γ. In both cell lines, pretreatment with IFN-γ markedly enhanced the ability of the TR60 receptor to mediate cell lysis. Conversely, under similar treatment conditions, the TR80 receptor did not appear capable of generating a cytolytic signal. Conclusions. TNF receptor modulation by IFN-γ appears to be unique to individual cell lines. The TR60 TNF receptor plays a central role in the synergistic cytolytic effects of IFN-γ and TNF-α. Sequential therapy with IFN-γ and TNF-α and specific TNF receptor activation may provide novel translational strategies for the use of cytokines in the treatment of ovarian cancer.