Members of the statin family of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors are being investigated for the therapy and prevention of cancers because of their growth-inhibitory effects on epithelial cells. Some epidemiologic studies show that patients taking statins show a lower incidence of cancer compared with those taking other cholesterol-lowering medication. In contrast, other studies show that statin use does not correlate with cancer risk. To address this discrepancy, we investigated the efficacy of different statins on the PC-3 prostate cancer cell line and the androgen-dependent LNCaP prostate cancer cell line. Clinically used statins, lovastatin, fluvastatin, and simvastatin inhibit proliferation of the two prostate cancer cells by inducing a G1 arrest. Lovastatin induced the arrest at 0.5 μmol/L, a concentration easily reached in the serum after oral administration. Pravastatin, however, was less effective at inhibiting 3-hydroxy-3-methylglutaryl CoA reductase in PC-3 cells and had to be present at 200 times higher concentrations to effect a cell cycle arrest. Another potential source of variability is the different levels of the cyclin-dependent kinase (cdk) inhibitor p27 noted in prostate cancers particularly because statins have been suggested to act through the induction of cdk inhibitors. All three statins (lovastatin, fluvastatin, and simvastatin) inhibited cyclin E/cdk2 kinase leading to hypophosphorylation of Rb, but this inhibition was correlated with a loss of the activating phosphorylation on Thr 160 of cyclin E-associated cdk2 and not dependent on the cdk inhibitors p2l and p27. Therefore, p27 status is unlikely to confound the epidemiologic data on the efficacy of statins in prostate cancer. To make definitive conclusions about the efficacy of statins on cancer prevention, however, the epidemiologic studies should take into account the type of statin used and the serum concentrations achieved and ensure that the tested statin inhibits the specific type of cancer in vitro at those concentrations. Copyright © 2006 American Association for Cancer Research.