We have recently shown that cisplatin increases the natural cytotoxic (NC) cell-mediated lysis of a variety of human adenocarcinoma cell lines that are resistant to cisplatin or NC activity alone. Because NC lysis is mediated by tumor necrosis factor alpha (TNF) bound to the surface of NC effector cells, we analyzed the ability of TNF in combination with cisplatin to increase the lysis of tumor cells. The in vitro anticancer potential of the combination of TNF and cisplatin was determined for both dividing and nondividing populations of two human ovarian carcinoma cell lines, SK-OV-3 and OVCAR-3. Nondividing SK-OV-3 and OVCAR-3 cells are resistant to cisplatin and TNF when used as single agents. Dividing OVCAR-3 cells are approximately two times more sensitive to TNF than dividing SK-OV-3 cells, whereas dividing SK-OV-3 cells are approximately ten times more sensitive to cisplatin than dividing OVCAR-3 cells. TNF at 1000 units/ml in the presence of clinically low concentrations of cisplatin (0.6-0.25 micrograms/ml) increased the lysis of dividing OVCAR-3 cells above the value expected for the sum lysis mediated by cisplatin alone and lysis mediated by TNF alone. Similar results were obtained with dividing populations of the SK-OV-3 cell line. The combination of cisplatin and TNF did not increase the lysis of the nondividing populations of either cell line. The increased lysis of tumor cells combined with the maintenance of specificity for only dividing cells indicates that the combination of cisplatin and TNF may be useful for the treatment of tumors that are resistant to either cisplatin or TNF.