The antifolate edatrexate has shown moderate activity against cancers of the head and neck and non-small cell lung cancer, as has cisplatin. Edatrexate demonstrates synergy with cisplatin in transplanted tumor models. This Phase I study was designed to evaluate two schedules of administration of cisplatin in combination with escalating doses of edatrexate, in a population consisting mainly of patients with these two cancers. The starting dose of edatrexate was 40 mg/m2. Dose escalation was to occur in 10-mg/m2 increments; the planned maximum dose level for study was 80 mg/m2. A total of 39 patients were registered. Eleven were treated on schedule A: cisplatin 120 mg/m2 every 4 weeks, and edatrexate weekly. Twenty-eight patients were assigned to schedule B: cisplatin 60 mg/m2 and edatrexate, both given every 2 weeks. On schedule A, the maximum tolerated dose of weekly edatrexate was 40 mg/m2, with dose-limiting toxicities of leukopenia, mucositis, and renal insufficiency. On schedule B, the maximum tolerated dose of biweekly edatrexate was 80 mg/m2, with leukopenia and mucositis as dose limiting. For schedule A, pharmacokinetic studies suggested a possible effect of cisplatin on the day 8 clearance of edatrexate. Studies on patients on schedule B did not show a clear effect of cisplatin on the day 15 edatrexate clearance. On schedule A, 5 of 9 evaluable patients had major responses (1 complete); whereas on schedule B, 8 of 25 patients had major responses (1 complete). Responses were seen in both head and neck and non-small cell lung cancer patients. For Phase II studies, use of cisplatin 60 mg/m2 and edatrexate 80 mg/m2, both given biweekly, is recommended.