The efficacy of tumor necrosis factor α (TNFα) as an anticancer agent is limited. This limitation might be related to the expression of a protein-synthesis-dependent resistance mechanism that prevents the lysis of tumor cells by TNFα. To test this possibility eight randomly selected human cell lines, three derived from ovarian carcinomas and five derived from cervical carcinomas, were tested for their in vitro sensitivity to TNFα-mediated lysis. The results of this analysis showed that all eight cell lines are normally resistant to lysis by TNFα. However, in the presence of inhibitors of protein synthesis, seven of them showed a significant increase in TNFα-mediated lysis. Measurement of protein synthesis showed that there is a linear correlation between the level of inhibition of protein synthesis and the level of TNFα-mediated lysis. The fact that seven of eight randomly selected cell lines are resistant to TNFα because they express a protein-synthesis-dependent resistance mechanism suggests that this mechanism of resistance may be common among gynecological cancers. The results also suggest that a therapy involving TNFα and inhibitors of protein synthesis might be useful for the treatment of gynecological malignancies.