HIV-1 cardiomyopathy has become a major cause of death in AIDS patients, but its pathogenesis is unclear. We used an antigen retrieval technique and immunostaining to investigate the hearts of 15 AIDS patients, of whom 3 had dilated cardiomyopathy. Immunocytochemistry shows infiltration of the left ventricular myocardium with mononuclear cells, ranging from minimal to diagnostic of myocarditis. The infiltrates include macrophages and CD3(+) and CD8(+) T cells. The tight junction protein ZO-1 is disrupted at the site of monocyte-macrophage vascular penetration and the coronary vessels show fibrinogen leakage in the hearts of AIDS patients, but not in the normal heart. A subset of infiltrating macrophages is doubly positive for cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase. HIV-1 peptides gp120 and Nef are expressed in macrophages and T cells, but not in cardiomyocytes. COX-2 is expressed by both gp120-positive and gp120-negative macrophages. The hearts of AIDS patients separate into those showing minimal infiltrates with low COX-2 expression and those with dense infiltrates and high COX-2; all failing hearts are in the latter group. These data suggest that COX-2-activated and HIV-1-infected monocyte-macrophages and T cells play a crucial role in the progression of HIV-1 myocarditis to HIV-1 cardiomyopathy.