T-cell adoptive immunotherapy for stringent murine tumor models, such as intracranial, s.c., or advanced pulmonary metastases, routinely uses lymphodepletive conditioning regimens before T-cell transfer, like recent clinical protocols. In this study, we examined whether host lymphodepletion is an obligatory component of curative T-cell therapy; we also examined the mechanism by which it augments therapy. Mice bearing intracranial, s.c., or 10-day pulmonary metastases of MCA 205 received total body irradiation conditioning or were nonirradiated before i.v. transfer of tumor-reactive T cells. Total body irradiation was not required for immunologically specific curative therapy and induction of memory provided that a 3- to 12-fold higher T-cell dose was administered. The mechanism involved enhanced intratumoral proliferation of T-effector cells in total body irradiation–conditioned recipients. In this tumor model, intratumoral T_reg cells were not detected; consequently, intratumoral T-effector cells produced identical amounts of IFN-γ upon ex vivo antigen stimulation irrespective of total body irradiation conditioning. Thus, host lymphodepletion augments T-cell immunotherapy through enhanced antigen-driven proliferation of T-effector cells, but curative therapy can be achieved in nonconditioned hosts by escalation of T-cell dose. These data provide a rationale for dose escalation of T-effector cells in situations where single or repeated lymphodepletion regimens are contraindicated.