Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to inhibit the in vitro and in vivo growth of a number of different cell lines. However, the mechanism by which lovastatin exerts its effect is not clear. In this experiment, we investigated the effect of lovastatin on the incorporation of [3H]thymidine by Hepatoma Tissue Culture- 4 (HTC-4) and Lewis Lung Carcinoma L-1 (LLC-L1) tumor cells. Tumor cells were grown under standard conditions and treated with four different concentrations of lovastatin. Cell growth was evaluated by daily hemacytometer cell counts. On Day 4, the plates were pulsed with 10 μCi [3H]thymidine. After 24 hr, the plates were harvested and [3H]thymidine incorporation was measured by scintillation counting. Lovastatin inhibited both HTC-4 and LLC-L1 cell growth in a dose-dependent manner. At the highest lovastatin dose, both LLC-L1 and HTC-4 cell growth was slowed to less than 15% of control. Remarkably, however, both cell lines showed a paradoxical, dose related, increase in [3H]thymidine uptake. Cell cycle analysis using flow cytometry was performed on Day 5 in the LLC-L1 cell line. As the lovastatin concentration increased, a lower percentage of cells was found in the G, phase of the cell cycle and a higher percentage of cells was found in the S and G2 phases. These findings suggest that these tumor cells are undergoing brisk DNA repair or that lovastatin is more effectively blocking cell division than cellular DNA replication.