Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) is a recognized but uncommon disease that is found to occur in patients with immunocompromised conditions such as acquired immunodeficiency syndrome (AIDS). These tumors may be multifocal and located at unusual sites, such as the brain and liver. This report describes the case of 2 AIDS patients with EBV-associated SMT and highlights the features and outcome of this rare but potentially important tumor in human immunodeficiency virus management.