Although cardiotoxic effects of highly active antiretroviral therapy (HAART) are a growing concern, there is a lack of prospective studies of subclinical involvement of the heart in human immunodeficiency virus (HIV)-infected patients. This study evaluated noninvasively cardiac morphologic characteristics and function in HIV-positive (HIV⁺) men receiving HAART for ≥2 years with no clinical evidence of cardiovascular disease. Echocardiography at rest, including tissue Doppler imaging and exercise testing, were performed in 30 HIV⁺ men (age 42.1 ± 4.7 years, duration of HIV infection 10.4 ± 4.7 years, duration of HAART 5.3 ± 2.1 years) and 26 age-matched healthy controls. At rest, HIV⁺ patients had similar left ventricular (LV) mass indexed to height^2.7 (40.6 ± 9.5 vs 37.5 ± 9.3 g/m; p >0.05), but a higher prevalence of LV diastolic dysfunction (abnormal relaxation or pseudonormal filling pattern in 64% of patients vs 12% of controls; p <0.001). LV systolic function indexes were significantly lower (ejection fraction 60.4 ± 8.7% vs 66.9 ± 6.9%; p <0.01, and tissue Doppler imaging peak systolic velocity 11.4 ± 1.6 vs 13.5 ± 2.2 cm/s; p <0.001). Pulmonary artery pressure was higher in patients compared with controls (32.1 ± 5.4 vs 26.1 ± 6.5 mm Hg; p <0.001). Exercise testing showed decreased exercise tolerance in HIV⁺ patients, with no case of myocardial ischemia. In conclusion, subclinical cardiac abnormalities are frequently observed in HIV⁺ patients on HAART. The usefulness of systematic noninvasive screening in this population should be considered. GECEM study no. 30: National Agency for AIDS Research (ANRS).