The antitumor activity of hexamethylmelamine (HMM) was evaluated using four human tumor xenografts serially transplanted in nude mice. HMM was dissolved in 0.2 ml of 1% hydroxypropyl cellulose per mouse and administered perorally daily, except on Sunday, for 4 weeks, giving an estimated maximum tolerated dose (MTD) of HMM of 75 mg/kg. The MX-1 cell line showed dose-dependent sensitivity to HMM and was completely eradicated by treatment at the MTD. The minimum effective dose of HMM against MX-1 was calculated to be 22.1 mg HMM/kg, resulting in the chemotherapeutic index of 3.4. The demethylated derivatives of HMM, pentamethylmelamine and tetramethylmelamine, were also effective against MX-1, whereas trimethylmelamine was ineffective. The effect of HMM was more marked when the drug was administered on day 1 after tumor inoculation, compared with administration during the exponential growth phase. HMM is thought to be a promising agent for the treatment of several types of human carcinoma, producing active metabolites in vivo after peroral administration.