Phosphonylmethoxyalkylpurine analogues were evaluated for their antitu-mor activity in murine tumor models. Three compounds, (S)-9-[(3-hydroxy-2-phosphonylmethoxy)propyl]adenine (HPMPA), 9-[(2-phosphonylmethoxy) ethyl]adenine (PMEA), and 9-[(2-phosphonylmethoxy)ethyl]guanine (PMEG) were modestly active with treated versus control (T/C) values of 125%–175% versus intraperitoneal P388 leukemia, but were inactive versus intravenously implanted P388. The most active and most potent of the three was PMEG, which was also evaluated against subcu-taneously (SC) implanted B16 melanoma. In confirmatory experiments, optimal therapy with PMEG yielded reproducible increases in life span (T/C values of 164%–170%) and delays in primary tumor growth (7.3- to 13.0-day T-C values). PMEG is representative of a new class of antitumor antimetabo-lites heretofore recognized only for their antiviral properties. [J Natl Cancer Inst 82: 510–512, 1990]