Pentamethylmelamine (PMM) is a water-soluble monodemethylated derivative of hexamethylmelamine and has a similar spectrum of activity against murine tumors. Unlike hexamethylmelamine, it is suitable for parenteral administration. We conducted a phase I trial of PMM given as a weekly 1-hour iv infusion to 34 extensively pretreated patients with advanced solid tumors. Eight dose levels ranging from 80 to 1500 mg/m2 were studied. A median of three infusions (mean, 4.2; range, 1-24) were given to each patient. Severe nausea and vomiting was dose-limiting at 1500 mg/m2; it was unresponsive to antiemetics and persisted up to 48 hours. Mild to moderately depressed levels of consciousness were seen in one third of the patients at dose levels of greater than or equal to 750 mg/m2. Consistent dose-related myelosuppression was not observed. Hepatocellular toxicity manifested by elevated serum transaminases occurred sporadically, usually in patients with liver metastases, but could not be unequivocally attributed to the drug. No complete or partial tumor responses were noted. At each dose level, the pharmacokinetics of PMM disappearance from plasma were studied in one to three patients with a gas chromatograph-mass spectrometer assay which exclusively measured the unmetabolized drug. The data obtained wee consistent with a two-compartment model of drug distribution, with a mean dose-independent terminal half-life of 143 minutes (range, 43-370). Peak drug levels were directly proportional to dose. The relative lack of myelotoxicity would make PMM an attractive candidate for addition to combination regimens if antitumor activity at tolerable doses could be documented. On this schedule, the recommended dose is 100 mg/m2 for phase II trials.