Radioimmunotherapy (RIT) has emerged as an effective treatment for lymphoma, however the underlying mechanisms are poorly understood. We therefore investigated the relative contributions of antibody and targeted radiation to the clearance of tumor in vivo, using 2 different syngeneic murine B-cell lymphoma models. Although RIT with (131)I-anti-major histocompatibility complex class II (MHCII) was effective in targeting radiation to tumor, no improvement in survival was seen by escalating the radiation dose alone and there were no long-term survivors. In contrast, using the combination of (131)I anti-MHCII in the presence of unlabeled anti-idiotype (anti-Id), 100% prolonged disease-free survival was seen in both B-cell lymphoma models at the higher radiation dose. Using in vivo tracking we show that treatment with radiation plus anti-Id monoclonal antibody (mAb) results in a substantially greater reduction of splenic tumor cells than with either treatment alone. Prolonged survival could also be achieved using (131)I anti-MHCII plus the signaling anti-CD19 mAb. Furthermore, the ability of these anti-B-cell mAbs to improve survival with targeted radiotherapy appeared to correlate with their ability to initiate intracellular signal transduction. Together these data illustrate that using 1 mAb to target radiation to tumor and a second to induce cell signaling is an effective new strategy in RIT.