3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, have been shown to positively impact vascular function independent of their plasma lipid-lowering action. Several of these beneficial effects involve modulation of gene expression. Here we explored whether the transcription factor Kruppel-like factor 2 (KLF2), a biomechanically activated gene we recently identified as part of the endothelial "atheroprotective phenotype," is regulated by statins and whether this mechanism is important for the non-lipid lowering beneficial effects mediated by these drugs in endothelium. The mRNA levels of KLF2 in human umbilical vein endothelial cells increased in the presence of various statins. KLF2 induction was observed within 8 h after drug treatment and remained elevated for at least 24 h. This statin effect on KLF2 expression was reversed by addition of mevalonate and its downstream metabolite geranygeranyl pyrophosphate. Furthermore, inhibition of protein geranylgeranylation with GGTI-298 significantly induced KLF2 levels, whereas inhibition of farnesylation did not. Statin-mediated KLF2 expression was followed by the up-regulation of several of its downstream transcriptional targets. Using small interfering RNA to block KLF2 expression, we demonstrated that this transcription factor is necessary for the statin-mediated regulation of several pathophysiologically relevant genes. These results strongly implicate KLF2 as a transcriptional regulator of the statin-mediated effects in vascular endothelium and provide a novel mechanism for the well established non-lipid lowering beneficial cardiovascular effects of statins.