We conducted a phase I study of CI-898 (trimetrexate), a new diaminoquinazoline antifolate in 22 patients with solid cancer in a multicenter collaborative study. The dosage schedule was single-dose intravenous administration (single treatment), followed by one or two courses of 5-day intravenous administration (5-day treatment) at 3-week intervals. Starting at 2 mg/m2 (1 n), the dose was increased up to 15 mg/m2 (7.5 n) for single treatment and 12 mg/m2 (6 n) for 5-day treatment. Evaluable cases numbered 18 for single treatment and 17 for 5-day treatment. In single treatment, the highest dose of 15 mg/m2 caused no serious side effect and did not reach the maximum tolerated dose (MTD). In 5-day treatment, leukocytopenia and thrombocytopenia were found dose dependently, the dose-limiting factor was bone marrow depression, and MTD was 10 mg/m2/day. The leukocyte and platelet counts reached the nadir in 1-3 weeks after initiation of 5-day treatment. The recovery from the nadir required about one week. Subjective side effects included mucitis (mouth, anus), malaise and gastro-intestinal symptoms (nausea, anorexia, diarrhea). None of alopecia, cardiotoxicity and nephrotoxicity were found. In the present phase I study, a tendency of tumor reduction was found in one case each of breast cancer (adenoma) and lung cancer (squamous cell carcinoma). The plasma concentration of the unchanged compound after single treatment showed a biphasic elimination pattern (t1/2 alpha 0.8-1.4 hr, t1/2 beta 9.4-13.0hr). The urinary excretion of the unchanged compound was 14.7-23.5% of the administered dose. In 5-day treatment, no accumulation was found. From the results of the present study, the recommended dosage of CI-898 in the early phase II study was considered to be 8 mg/m2/day intravenously for 5 days (every 3-4 weeks).