Rationale: Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) are rare, virally-induced malignancies that occur almost exclusively in immunocompromised individuals. We report a very rare case of a dura-based EBV-SMT with superimposed local cryptococcal infection.Patient concerns: An adult male with a history of untreated acquired immunodeficiency syndrome presented to our hospital with worsening headaches, diarrhea, and diffuse myalgias.Diagnoses: Blood cultures were positive for methicillin-resistant Staphylococcus aureus and Cryptococcus neoformans serum antigen. Magnetic resonance imaging revealed 2 adjacent enhancing masses in the right temporal lobe, perilesional edema, and mass effect of the right lateral ventricle. Histological examination and immunohistochemical stains of the surgical specimen were consistent with EBV-SMT. Cryptococcus organisms were identified within the neoplasm. Interventions:The patient underwent complete tumor resection, received an extended course of amphotericin and flucytosine, and was restarted on antiretroviral therapy.Outcomes: The patient was discharged from the hospital with no focal neurological deficits.Lessons: Epstein-Barr virus associated smooth muscle tumors are rare malignancies that occur in immunocompromised patients. Prognosis is largely dependent on immune reconstitution and treatment of concomitant infections. Abbreviations: AIDS = acquired immunodeficiency syndrome, CNS = central nervous system, EBV-SMT = Epstein-Barr Virusassociated smooth muscle tumor, HIV = human immunodeficiency virus, MRSA = methicillin-resistant Staphylococcus aureus, POD = postoperative day.