Epstein-Barr virus (EBV) infection and latency has been associated with malignancies, including nasopharyngeal carcinoma and Burkitt's lymphoma. EBV encoded latent membrane protein 2A (LMP2A) is expressed in most EBV-associated malignancies and as such provides a therapeutic target. Burkitt's lymphoma is a hematopoietic cancer associated with the translocation of c-MYC to one of the immunoglobulin gene promoters leading to abnormally high expression of MYC and development of lymphoma. Our laboratory has developed a murine model of EBV-associated Burkitt's lymphoma by crossing LMP2A transgenic mice with MYC transgenic mice. Since LMP2A has been shown to activate the PI3K/Akt/mTOR pathway, we tested the therapeutic efficacy of mTOR inhibitor rapamycin on the tumors and splenomegaly in these double transgenic mice (Tg6/λ-MYC). We found that rapamycin reversed splenomegaly in Tg6/λ-MYC mice prior to tumor formation by targeting B cells. In a tumor transfer model, we also found that rapamycin significantly decreased tumor growth, splenomegaly, and metastasis of tumor cells in the bone marrow of tumor recipients. Our data show that rapamycin may be a valuable candidate for the development of a treatment modality for EBV-positive lymphomas, such as Burkitt's lymphoma, and more importantly, provides a basis to develop inhibitors that specifically target viral gene function in tumor cells that depend on LMP2A signaling for survival and/or growth.