Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMT), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus (HIV) infection and post-transplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome (AIDS) they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report two distinct cases of EBV-related SMT, unique through their co-associated immunosuppressive state or location: the first occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation (SCT); the second developed in the orbit after heart transplant.