Nonmyeloablative allogeneic stem cell transplantation (NST) is thought to be an immunologic therapy in which donor T cells mediate a graft-versus-tumor effect. We recently reported the clinical outcome of a phase II trial of NST in metastatic renal cell carcinoma (RCC). However, the immune response correlates of clinical activity remain unknown. We now describe the analysis of T-cell subsets and T-cell cytokine-producing potential for those patients evaluable for immune monitoring. The incidence of graft-versus-host disease (GVHD) correlated with clinical outcome, with all responders exhibiting chronic GVHD. Following initial tapering of immunosuppression, an increase in the total numbers of CD8+ T cells but not CD4+ T cells was observed among responders compared to nonresponders. In addition, a greater ratio of CD8+ to CD4+ T cells producing IFN-gamma and IL-2 was seen in clinical responders at the time when clinical responses were first detected (day 180 after transplantation). Our results support the hypothesis that the antitumor effects of NST may be mediated by IFN-gamma-producing CD8+ T cells, and indicate that isolation of putative tumor antigen-specific T cells, ideally, should be pursued around day +180.