BACKGROUND AND AIMS: Aortic valve stenosis (AVS) affects a significant percentage of our elderly population and younger subjects with familial hypercholesterolemia. Lipoprotein(a) [Lp(a)] has been associated with AVS in recent genetic studies. The purpose of this study was to determine the effects of Lp(a) on human aortic valve interstitial cells (HAVICs), and to identify apolipoproteins and phospholipids in diseased human aortic valves. METHODS: We examined the effects of Lp(a) on HAVICs mineralization and oxidant formation. Proteomic analyses were used to determine the effects of Lp(a) on downstream intracellular markers. We also used mass spectroscopy to identify the different lipoproteins and oxidized phospholipids in calcified aortic valves. RESULTS: HAVICs incubated with either LDL or Lp(a) had significantly higher calcium deposition, compared to control (p<0.001), with Lp(a) having the most significant effect (p<0.01) compared to LDL. Proteomic analysis after 10 days of treatment with Lp(a) resulted in enrichment of proteins involved in calcium deposition and vesicle biogenesis. Treatment of HAVICs with Lp(a) significantly increased ROS formation (p<0.05). Patients with calcific aortic stenosis had higher plasma Lp(a) concentrations compared to non-CAD individuals (p<0.001). LC-MS/MS revealed the presence of apolipoproteins and phospholipids in calcified human aortic valves. CONCLUSIONS: The present study outlines an association between Lp(a) and AVS, and suggests that Lp(a) may serve as a potential target for therapeutic purposes to manage the progression of AVS.