Infective endocarditis results in the growth of a vegetative mass on native or bio prosthetic valves hindering function and increasing risk of thromboses. This study set out to determine the proteomic composition of these vegetations including the influence of different micro-organisms and the proteases known to be present. Our data has allowed us to describe for first time the influence different infectious organisms have on vegetation growth. Including the contribution of the immune response and circulatory proteins/cells make in composing a vegetation. Furthermore, we describe the protease activity and both known and novel cleavage sites in a plethora of targets. This data provides a deep insight into the homogeneity and heterogeneity of vegetation composition.