As more effective therapies have produced longer survival times for HIV-infected patients, non-infectious complications of late stage HIV infection such as the development of severe global left ventricular dysfunction (dilated heart muscle disease) have emerged. The demographic and clinical characteristics of HIV-infected patients who develop dilated heart muscle disease as well as potential risk factors are, as yet, poorly characterized. Of 174 patients enrolled in a prospective longitudinal study, a total of nine patients, all with CD4 T cell counts < 200 mm-3, developed symptomatic heart disease (congestive heart failure n = 7, sudden cardiac death n = 1 and cardiac tamponade n = 1); three of these patients developed progressive cardiac dysfunction leading to primary cardiac failure and death. An additional 55 HIV-infected patients referred to our Cardiomyopathy Service were found to have global left ventricular dysfunction, with 84% having New York Heart Association Class III or IV congestive heart failure on presentation. Clinical characteristics associated with severe symptomatic cardiac dysfunction included low CD4 T cell counts, myocarditis associated with non-permissive cardiotropic virus infection on endomyocardial biopsy and persistent elevation of anti-heart antibodies. No relationships to any specific HIV risk factor or opportunistic infection were found. These findings suggest that a severe form of HIV-related dilated heart muscle disease is largely a disease of late stage HIV infection. Virus-related myocarditis and cardiac autoimmunity may play a role in the pathogenesis of progressive cardiac injury. Long-term longitudinal studies of larger HIV-infected cohorts are warranted to identify clinical, behavioral and immunologic risk factors.