Numerous epidemiological studies have demonstrated that consumption of large quantities of vegetables and fruits reduces the risk of human cancer. The anti-cancer properties of the major tomato carotenoid, lycopene, have recently been reported. In previous studies we have found that lycopene inhibits proliferation of a variety of human cancer cells in culture including breast (MCF-7), endometrial (Ishikawa), lung (NCI-H345) and white blood cells (HL-60), but has almost no effect on growth of human fibroblasts. The aim of this study was to analyze the mechanism of cancer cell growth inhibition by lycopene. This inhibition was accompanied by neither necrotic nor apoptotic cell death. For this reason the potential effect of lycopene on cell cycle progression was studied. Lycopene attenuated cell cycle progression in linear growing HL-60 cells by increasing the amount of cells remaining in the GQ-GI phase with a corresponding decrease in the S phase. We were unable, however, to observe such an effect in non-synchronized MCF-7, Ishikawa and NCI-H345 cells. Therefore MCF-7 mammary cancer cells were synchronized in late G i phase by incubation for 24 hours with the plant amino acid mimosine. The cells were readily released from the block after removal of mimosine. Ten hours after the release, 80% of the cells were in S phase and only 10% remained in the GI phase. However, when the cancer cells were incubated with both mimosine and lycopene, release from the block by removal of mimosine was significantly delayed. This lycopene-induced delay in S phase progression was observed also in lung and endometrial cancer cells. In order to check whether the two compounds act on a similar component of the cell cycle machinery, the effect of low concentrations of lycopene (0.4 uM) and mimosine (100 uM) on [3H]thymidine incorporation was studied. When applied separately, the two compounds had only a moderate effect on [3H]thymidine incorporation. However, combination of lycopene and mimosine at those low concentrations resulted in a marked synergistic inhibition. The results suggest that lycopene affects cell growth by inhibiting the cell cycle during the transition from GI to S phase, although its exact point of intervention may differ from that of mimosine.