Autopsy studies of AIDS (acquired immune deficiency syndrome) patients showed a high incidence of myocarditis. To attain a better understanding of the pathogenesis, the pathology and immunopathology of nine endomyocardial biopsies with active myocarditis from 18 human immunodeficiency virus (HIV)-positive patients were systematically characterized. These were compared with 17 biopsies with active myocarditis from patients without AIDS risk factors. In both groups, the myocarditis consisted of either multifocal or interstitial infiltrates of small lymphocytes and isolated myocyte necrosis. The lymphocytes consisted of T cells (CD2+, CD3+) and cells not identified by the usual markers. B cells, monocytes, CD4+ cells, and natural killer (NK) cells were only rarely observed. All of the HIV-positive patients but only 7 of 17 non-HIV patients had CD8+ lymphocytes in the infiltrates (P less than 0.01). The arteriolar endothelium demonstrated induced class I (HLA-A, B, C) and II (HLA-DR) antigens in both groups. In situ hybridization for HIV-1 failed to identify the virus in the specimens. The immunopathology is consistent with a cell-mediated injury to the myocytes in HIV-positive patients and is similar to a subgroup of myocarditis in the non-HIV group.