Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B-cell malignancies, although many still relapse and little progress has been made with T-cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhance antitumor immune responses using novel immunomodulatory agents in combination with standard of care treatments. Here we report that intravenous administration of the Toll-like receptor 7 (TLR7) agonist, R848 in combination with radiation therapy (RT), leads to the longstanding clearance of tumor in T- and B-cell lymphoma bearing mice. In combination, TLR7/RT therapy leads to the expansion of tumor antigen-specific CD8(+) T cells and improved survival. Furthermore, those mice that achieve long-term clearance of tumor after TLR7/RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response. Our findings demonstrate the potential for enhancing the efficacy of conventional cytotoxic anticancer therapy through combination with a systemically administered TLR7 agonist to improve antitumor immune responses and provide durable remissions.