Background: Calcific aortic stenosis may have common etiological factors with atherosclerosis. Hypothesis: In this retrospective, case-control study, we aimed to determine whether there is an association between hypercholesterolemia and calcific aortic valve stenosis. Methods: Consecutive patients undergoing single aortic or mitral valve replacement in a regional cardiothoracic surgical center were reviewed and preoperative patient characteristics were recorded: demographics, comorbidity (including coronary artery disease and associated risk factors), serum total cholesterol, lipid-lowering therapy, and serum creatinine. Results: Serum total cholesterol concentrations were significantly higher in patients with calcific aortic stenosis than in controls (6.2 +/- 1.1 vs. 5.3 +/- 1.1 mmol/l; p <0.001). The significant difference in serum cholesterol concentrations remained following collection for gender and body mass index (p = 0.02) and when patients: with coronary artery disease were excluded (6.3 +/- 1.1 vs. 5.3 +/- 1.4 mmol/l; p <0.001). Subgroup analysis demonstrated that the association between elevated serum cholesterol concentrations and calcific aortic stenosis was particularly strong in patients with tricuspid aortic valves (6.4 +/- 1.2 vs. 5.3 +/- 1.1 mmol/l; p <0.001) compared with those with bicuspid valves (5.9 +/- 1.1 vs. 5.3 +/- 1.1 mmol/l; p = 0.06). Conclusions: We conclude that hypercholesterolemia is associated with calcific aortic stenosis and may be implicated in its pathogenesis and profession. We believe that there is now a need for a randomized, controlled trial of cholesterol-lowering therapy in patients with calcific aortic stenosis.