A total of 15 patients with advanced neoplastic disease, 13 with different solid tumors, one with lymphoma, and one with acute lymphocytic leukemia, underwent treatment consisting of continuous infusion of methotrexate (2 g/sq m/day) with concomitant thymidine (8 g/sq m/day) and leucovorin (1 mg/sq m/day). The dose of methotrexate was increased progressively by lengthening the methotrexate infusion from 2 to 7 days. After cessation of methotrexate infusion, thymidine and leucovorin were continued until the plasma level of methotrexate decreased to 2 X 10(-8) M. Toxicity was mucositis (23 of 27 evaluable courses), leukopenia (15 of 26 evaluable courses), thrombocytopenia (10 of 26 evaluable courses), renal and hepatic toxicity and diarrhea. Plateau levels of plasma methotrexate or methotrexate plasma half-life did not correlate with toxicity.