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Both gemcitabine (2',2'-difluorodeoxycytidine; dFdC) and cisplatin (cis-diammine dichloroplatinum; CDDP) are active against several solid malignancies, including ovarian cancer and head and neck squamous cell carcinoma. Because of differences in mechanisms of action and toxicity profiles, combination of the two drugs has enormous clinical potential. We studied possible synergism between the drugs: in vitro using three variants of the human ovarian cancer cell line A2780, and in vivo using gemcitabine- and cisplatin-sensitive and -resistant tumors, the head and neck cancer xenografts HNX-22B and HNX-14C and the murine syngeneic colon 26-10 tumor. In vitro, cells were cultured for 72 hours and exposed to the drugs for 1 to 72 hours; synergy was evaluated by multiple drug-effect analysis. In wild-type A2780 and cisplatin-resistant ADDP cells, simultaneous exposure for 24 and 72 hours was synergistic, as well as preincubation with cisplatin for 4 hours followed by gemcitabine. Preincubation with gemcitabine for 4 hours followed by gemcitabine and cisplatin was synergistic in ADDP and A2780 cells. Cisplatin did not enhance the accumulation of gemcitabine triphosphate in A2780 and ADDP cells. Cisplatin caused a marginal decrease of the number of double strand breaks in the DNA caused by gemcitabine. In vivo, gemcitabine at the maximum tolerated dose of 100 or 120 mg/kg could be combined with cisplatin at 4 mg/kg. When injected simultaneously this resulted in at least additive anti-tumor activity in HNX-22B, but not in HNX-14C and colon 26-10 tumors. Cisplatin, injected 4 hours before or after gemcitabine, was equally active as the simultaneous schedule in HNX-22B tumors, but more toxic. In conclusion, the combination of gemcitabine and cisplatin can be synergistic in vitro and at least additive in vivo; this synergism is schedule dependent. The mechanism cannot be explained by gemcitabine triphosphate accumulation or DNA damage studies.