Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. Effects of gamma-tocopherol on the cell cycle and proliferation were examined in human prostate carcinoma, colorectal adenocarcinoma, and osteosarcoma cells. Many epidemiological studies have suggested an anticancer activity of vitamin E, yet mechanistic studies are sparse to date. Vitamin E consists of four tocopherols (alpha-, beta-, gamma-, delta-) and the corresponding tocotrienols. Because gamma-tocopherol is the predominant form of tocopherol found in the U.S. diet, while alpha-tocopherol is the form of vitamin E most readily found in dietary supplements, we compared physiologically relevant concentrations of these tocopherols and found a more significant growth inhibition effect for gamma- than for alpha-tocopherol. Flow cytometry analysis of gamma-tocopherol treated prostate carcinoma DU-145 cells showed decreased progression into the S-phase. This effect was associated with reduced DNA synthesis as measured by 5-bromo-2'-deoxy-uridine incorporation. Furthermore, Western-blot analysis of gamma-tocopherol treated cells showed decreased levels of cyclin D1 and cyclin E. Taken together, the results indicate that gamma-tocopherol inhibits cell cycle progression via reduction of cyclin D1 and cyclin E levels. Because gamma-tocopherol has a weaker antioxidant capacity than a-tocopherol and gamma-tocopherol more significantly inhibited cell proliferation as well as DNA synthesis than alpha-tocopherol, we suggest a non-antioxidant mechanism to be at the basis of this effect.