We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR(+) T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR(+) T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR(+) T cells from the lungs, enhanced T-cell survival, and promoted cTCR(+) T cell-dependent elimination of established mouse CD20(+) leukemia. Furthermore, CD20-specific cTCR(+) T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR(+) T cells to survive and control tumors.