Histological demonstration of microorganisms, vegetations, or active endocarditis in cardiac valve tissue is included in the Duke criteria and is considered to be a criterion of confirmed infective endocarditis. However, the histological features that characterize infective endocarditis are not accurately defined at the qualitative and quantitative levels.Pathologic analysis of tissue adjoining mechanical cardiac valves was undertaken retrospectively for 21 patients who underwent surgical removal of a mechanical valve because of suspected infective endocarditis and 69 patients who underwent surgical removal of a mechanical valve because of noninfectious dysfunction. To better define the histological criteria for infective endocarditis, we used quantitative image analysis to compare these 2 groups of patients with respect to valvular fibrosis, calcifications, vegetations, patterns of inflammation, and vascularization.Histologically, infective endocarditis in patients with mechanical valves was characterized by the demonstration of microorganisms, vegetations, and significant neutrophil-rich inflammatory infiltrates with extensive neovascularization. In contrast, valve tissue specimens from patients with mechanical valves that were removed because of noninfectious complications showed significant rates of extensive fibrosis and, when present, inflammatory infiltrates that were mainly composed of macrophages and lymphocytes. A neutrophil surface area with a cutoff value of > or =2% of the total valve tissue surface is highly predictive of (90%) and specific for (98%) infective endocarditis.When no microorganisms are detected and vegetations are lacking in tissue adjacent to a mechanical valve, neutrophil-rich inflammation and extensive neovascularization might better histologically define the term "active endocarditis" in the Duke criteria. This definition would allow differentiation between infective endocarditis and inflammatory noninfectious valve processes in patients with mechanical cardiac valves.