Disease relapse remains a principle cause of mortality following autologous hematopoietic transplant. Strategies to enhance immune function in the post-transplant setting are needed to eliminate residual disease. CD40 stimulation through the use of agonistic CD40 antibodies has been shown to promote anti-tumor activity both as a single agent and in combination with IL-2 administration with increases in dendritic cell numbers being observed. We hypothesized that CD40 stimulation in combination with myeloablative syngeneic hematopoietic cell transplantation can act together to promote anti-tumor responses. We developed a model in which anti-CD40 given with syngeneic BMT was assessed in advanced tumor-bearing mice. We have found that delaying administration of anti-CD40 for one week post-BMT could obviate the severe toxicity associated with immediate post-BMT administration. BALB/c were given a syngeneic renal cell carcinoma cell line (Renca) i.v. After 4 days, at which time lung metastases were established, the mice were treated with syngeneic BMT followed one week later with initiation of anti-CD40 treatment (100 μg/dose; daily, 4 days per week for 2 weeks). CD40 stimulation resulted in significant expansion of GR-1+/CD11b+ myeloid and CD11c+/I-A+ dendritic cells in the spleen, similar to the expansion of these populations observed in mice that received anti-CD40 and no BMT. However, while B220+ IgM+ B cells are significantly expanded following anti-CD40 administration in mice that do not receive a transplant, B cell recovery is reduced following transplant in mice that also received anti-CD40. T cell recovery post-transplant did not differ significantly in animals that received anti-CD40 or control antibody. Importantly, significant increases in survival of anti-CD40 treated, tumor-bearing recipients of syngeneic BMT were observed compared to either treatment alone (log-rank test p< 0.001). This promotion of anti-tumor activity by CD40 stimulation was seen in mice that were profoundly T cell deficient due to the transplant. These data suggest that despite severe immune depletion that occurs after lethal TBI, immunomodulation by anti-CD40 can result in significant protection from the residual disease despite the severe lack of T cells at this time period.