HMG-CoA reductase inhibitors (statins) have been shown to inhibit angiogenesis. The molecular mechanism mediating the anti-endothelial activities of statins remains unclear. The present study demonstrated that the antiangiogenic effect of atorvastatin (ATV) was associated with endothelial death. Molecular profiling data identified a 29-fold upregulation of beta4 integrin mRNA. Western blot and flow cytometry confirmed robust increases of total and cell-surface beta4 integrin. Blockage of beta4 integrin activity by antagonizing antibody abrogated ATV-induced endothelial death. The endothelial death and beta4 integrin upregulation by ATV could be reversed by intermediate metabilites of the HMG-CoA reductase pathway mevalonate or GGPP, but not by FPP, suggesting that these effects were results of specific inhibition of the pathway. These data indicate that the HMG-CoA reductase might represent an important survival pathway in angiogenic endothelial cells and thus, a potential target for antiangiogenic therapy.