The ability of human chorionic gonadotropin (hCG) to modify prostate carcinoma viability in vitro and in vivo when combined with the HMG CoA reductase inhibitor lovastatin and ionizing radiation was investigated. Treatment of PC-3 cells in vitro with hCG caused a modest increase in numbers of non-viable cells within 96 h. Treatment of cells with hCG followed by exposure to the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The cytotoxic effects of hCG were blocked by expression of BCL-(XL) and dominant negative caspase 9. Treatment of mice bearing PC-3 flank tumors with lovastatin and hCG significantly reduced tumor volume within 7 days; this was also reflected in decreased ex vivo colony survival of the cells which correlated with increased cleavage of pro-caspase 3 and reduced Ki67 immuno-reactivity. In vitro, treatment of PC-3 cells with hCG followed by exposure to ionizing radiation enhanced the cytotoxic effects of hCG, that was further enhanced by lovastatin. In vivo, hCG radiosensitized PC-3 tumors and significantly enhanced the lethality of hCG and lovastatin treatment. Collectively, our findings argue that treatment of PC-3 prostate cancer tumors with hCG, lovastatin and radiation represents a potential novel therapeutic approach.