Heart valve dysfunction is a relatively common condition in the population, whereas significant heart valve disease is more unusual. The cause of different types of heart valve disease depends on which valve is concerned. Rheumatic heart valve disease, has for a long time been considered to constitute a post-inflammatory condition. During the 1990s it was also shown that the so-called non-rheumatic or degenerative tricuspid aortic stenosis, comprised signs of inflammation. In this study, 118 patients (the VOCIN study group) referred to the University Hospital for preoperative investigation due to significant heart valve disease, were examined regarding signs of inflammation. Twenty-nine aortic valves from patients with significant aortic stenosis were divided into tricuspid and bicuspid aortic valves. The bicuspid aortic stenotic valves revealed signs of inflammation to a similar extent as the tricuspid valves. However, the tricuspid and bicuspid valves differed regarding distribution of calcification. In contrast, inflammation was not a predominant feature in 15 aortic and mitral valves from patients with significant heart valve regurgitation. Gross valvular pathology consistent with rheumatic aortic stenosis was found in 10 patients. These valves revealed a somewhat lower degree of inflammatory cell infiltration, but on the whole, there were no substantial differences when compared to non-rheumatic aortic stenotic valves. They did, however, reveal a similar distribution of calcification as the bicuspid, non-rheumatic aortic valves. The VOCIN study group was compared to an age- and gender matched control group with regard to history and signs of rheumatic disease. There was not any increased prevalence of clinical manifestations of non-cardiac inflammatory disease in patients with significant heart valve disease, when compared to healthy control subjects. However, patients with heart valve disease had significantly increased serum levels of inflammatory markers compared to controls. The increase in inflammatory markers remained significant even in the subgroup of non-rheumatic aortic stenosis devoid of coronary artery disease. These results indicate that a systemic inflammatory component is associated with stenotic, non-rheumatic heart valve disease. The similarities between different forms of calcific aortic valve disease indicate a similar pathogenesis. The question is raised whether aortic stenosis is one disease, mainly caused by a general and non-specific response to dynamic tissue stress due to an underlying malformation of the valve.