Adoptive transfer of allogeneic T cells has unmatched efficacy to eradicate leukemic cells. We therefore sought to evaluate in kinetic terms interactions between T cells and allogeneic leukemic cells. T cells primed against the model B6^dom1 minor histocompatibility antigen were adoptively transferred in irradiated B10 (B6^dom1-positive) and congenic B10.H7^b (B6^dom1-negative) recipients, some of which were also injected with EL4 leukemia/lymphoma cells (B6^dom1-positive). A key finding was that the tissue distribution of the target epitope dramatically influenced the outcome of adoptive cancer immunotherapy. Widespread expression of B6^dom1 in B10 recipients induced apoptosis and dysfunction of antigen-specific T cells. Furthermore, in leukemic B10 and B10.H7^b hosts, a massive accumulation of effector/memory B6^dom1-specific T cells was detected in the bone marrow, the main site of EL4 cell growth. The accumulation of effector/memory cells in recipient bone marrow was EL4 dependent, and its kinetics was different from that observed in recipient spleen. We conclude that strategies must be devised to prevent apoptosis of adoptively transferred T cells confronted with a high antigen load and that local monitoring of the immune response at the site of tumor growth may be mandatory for a meaningful assessment of the efficacy of adoptive immunotherapy.