Dilated cardiomyopathy is a syndrome characterized by cardiac enlargement and impaired systolic function of the heart. Tumor necrosis factor (TNF)-α, a pleiotropic cytokine, seems to play a central role in the progression of dilated cardiomyopathy. Recent data suggest that ongoing inflammation in the myocardium may, in many cases, contribute to the development of disease. Chronic generation of autoantibodies to myocardial antigens or, in some cases, viral infection are pathobiologically involved. Although both antibodies and some viruses activate the complement system, the role of innate immunity in dilated cardiomyopathy has as yet not been investigated systematically. In this study we demonstrate by analysis of myocardial biopsies from 28 patients that C5b-9, the terminal membrane attack complex of complement, accumulates in human myocardium in dilated cardiomyopathy. C5b-9 significantly correlates with immunoglobulin deposition and myocardial expression of TNF-α. In vitro, C5b-9 attack on cardiac myocytes induces nuclear factor (NF)-κB activation as well as transcription, synthesis, and secretion of TNF-α. We conclude that chronic immunoglobulin-mediated complement activation in the myocardium may contribute in part to the progression of dilated cardiomyopathy via C5b-9-induced TNF-α expression in cardiac myocytes.