Cardiac effects of human immunodeficiency virus (HIV) transactivator (Tat) are unclear, but Tat decreases liver glutathione (an important mitochondrial antioxidant) when ubiquitously expressed in transgenic mice (TG). With an alpha-myosin heavy chain promoter, Tat was selectively targeted to murine cardiac myocytes. One high-expression hemizygous ((+/-)Tat(high); 12 copies) and two low-expression ((+/-)Tat(lowA,B); 2-5 copies) TG lines were created. Cardiomyopathy was documented with increased left ventricle (LV) mass, ventricular expression of atrial natriuretic factor (ANF) mRNA, mitochondrial ultrastructural defects, and myocardial depletion of glutathione. In (+/-)Tat(high) TGs, normalized LV mass (determined echocardiographically) increased 46% (90 days), 134% (240 days), and 96% (365 days) compared with wild-type littermates (WT). LV fractional shortening was decreased to 28% (90 days), 27% (240 days), and 19% (365 days). (+/-)Tat(low) LV mass was unchanged (or=210 days); however, profound mitochondrial destruction occurred in homozygous (+/+)Tat(high) hearts (10 days) and the pups died (14 days). Tat caused cardiac dysfunction in this TG and may impact on cardiomyopathy in acquired immunodeficiency syndrome.