Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinoma, some Burkitt's-type lymphomas, and posttransplantation lymphoproliferative disorder. Recently, an association between EBV and smooth muscle tumors, both malignant and benign, in the acquired immunodeficiency syndrome and posttransplantation populations has been made. We report, to our knowledge, the first case of a renal EBV-associated smooth muscle tumor. A 33-year-old man with acquired immunodeficiency syndrome presented with a mass of the left kidney that was radiographically suspicious for malignancy. He underwent left radical nephrectomy. The tumor measured 3.0 cm in the largest dimension, was well-circumscribed, and was composed of fascicles of bland spindle cells with blunt-ended nuclei, which often intersected at right angles. Focal areas of cell crowding and nuclear pleomorphism were present. No areas of lipomatous differentiation were identified. Immunohistochemically, the tumor cells were positive for desmin and muscle-specific actin and were negative for HMB-45 and CD21 (an EBV receptor). In situ hybridization with EBV-encoded RNA-1, a probe that recognizes a non-poly(A) RNA EBV transcript expressed in latently infected cells, was diffusely positive. At 6 months postnephrectomy, the patient showed no evidence of local recurrence or metastases. The incidence of this tumor is expected to increase as both the numbers of patients undergoing solid organ transplantation and the survival time of patients with the acquired immunodeficiency syndrome increase. A better understanding of the biology and pathogenesis of this entity will be important for future management of these patients.