Pentamethylmelamine (PMM), a demethylated soluble analog of hexamethylmelamine, was given to 35 patients with solid tumors in a phase I clinical trial. Thirty patients were given single doses ranging from 80 to 2000 mg/m2 in a 2-hour infusion every 3 weeks. Once a maximum tolerated dose was defined for this schedule, an additional five new patients plus four patients who had already received PMM were treated on a multiple-dose schedule of PMM given three times a week every Monday, Wednesday, and Friday (M-W-F) for 4 weeks. Dose-limiting toxic effects for the single-dose schedule were in the central nervous system and gastrointestinal tract, manifested by nausea (60%), vomiting (49%), somnolence (37%), depression (6%), and headache (6%). Other toxic effects observed on this schedule included anorexia (34%), diarrhea (7%), and diaphoresis (21%). The toxic effects were first observed in mild form at 400 mg/m2/dose and became progressively more severe and prolonged with each dose escalation; they were considered intolerable at the 2000-mg/m2 dose level in all patients treated. The nine patients receiving the multiple-dose schedule were given PMM at a dose of 1000 mg/m2 three times a week (M-W-F). This level produced dose-limited nausea and vomiting in all patients so that no patient completed greater than 3 weeks of treatment on this schedule. One patient developed PMM-related visual hallucinations. PMM produced no hematologic, hepatic, renal, allergic, or acute side effects; no alopecia was observed. Minor tumor regressions of 1 month's duration were seen in two patients, one with pleural mesothelioma and one with a parotid gland tumor. The recommended doses for solid tumor phase II studies are 1500 mg/m2 given as a 2-hour infusion every 3 weeks and 1000 mg/m2 given three times a week (M-W-F), repeated at 3-week intervals.