EBV positive smooth muscle tumors are a rare oncological entity that can develop in secondary immunodeficiency such as human immunodeficiency virus-infection or solid organ transplantation. In addition, in rare pediatric cases EBV positive smooth muscle tumors can develop in the context of primary immunodeficiency such as CARMIL2 deficiency. In secondary immunodeficiency and when the underlying condition can not be cured, the treatment of EBV positive smooth muscle tumors is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. However, when cellular immunity cannot be reestablished or EBV positive smooth muscle tumors cannot completely be resected, long-term survival is poor. Importantly, allogeneic hematopoietic blood stem cell transplantation resulted in cure of immunodeficiency and EBV positive smooth muscle tumors in a GATA-2 deficient patient and is ongoing in a CARMIL2 deficient patient. Thus, in the absence of secondary immunodeficiency patients presenting with EBV positive smooth muscle tumors should be thoroughly evaluated for primary immunodeficiency disorders and patients with known primary immunodeficiency presenting with smooth muscle tumors should be evaluated for an underlying ectopic EBV infection. Allogeneic hematopoietic stem cell transplantation should be taken into consideration in these cases.