Although the frequent occurrence of meniscal degeneration is a well-known fact and its consequences include rupture and even loss of the meniscus, the pathogenetic factors are established insufficiently. Because complement factors and leukocytes are present in synovial fluid, we tried to detect complement deposits and macrophages in menisci, which displayed degenerative changes. We therefore performed a retrospective analysis by immunohistochemical staining of C4d and CD68 in meniscal tissue derived from patients (n=15) who underwent meniscectomy because of meniscal tears and from three autopsy cases (n=3). In this study, focal C4d deposits in the meniscal extracellular matrix in areas of mucoid degeneration or fibrillation were demonstrated for the first time, while no C4d deposits in the avascular zone of menisci without signs of degeneration or injury could be detected. In addition, colocalization of C4d and CD68+ cells was found at sites of meniscal tissue disintegration in five cases. These results represent the first evidence for an involvement of complement and macrophages in meniscal tissue disintegration, indicating a complement mediated reaction at the site of tissue alteration.