This study shows that DKK-1, a member of the Dickkopf family and a regulator of the Wnt pathways, represents a novel target of statins which, through the inhibition of HMG-CoA reductase and of non-steroidal isoprenoid intermediates, exert extra-beneficial effect in preventing atherosclerosis beyond their effect on the lipid profile. We found that atorvastatin downregulates DKK-1 protein (-88.3 ± 4.1%) and mRNA expression (-90 ± 4.2%) through the inhibition of Cdc42, Rho and Rac geranylgeranylated proteins. Further, a combined approach based on the integration of label-free quantitative mass spectrometry based-proteomics and gene silencing allowed us to demonstrate that DKK-1 itself mediates, at least in part, statin effects on human endothelial cells. Indeed, DKK-1 is responsible for the regulation of the 21% of the statin-modulated proteins, which include, among others, clusterin/apoJ, plasminogen activator inhibitor type 1 (PAI-1), myristoylated alanine-rich C-kinase substrate (MARCKS), and pentraxin 3 (PTX3). The Gene Ontology enrichment annotation revealed that DKK-1 is also a potential mediator of the extracellular matrix organization, platelet activation and response to wounding processes induced by statin. Finally, we found that plasma level of DKK-1 from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) was lower (-42 ± 23%) than that of control animals. Thus, DKK-1 is not only a target of statin but it directly regulates the expression of molecules involved in a plethora of biological functions, thus expanding its role, which has been so far restricted mainly to cancer.