Despite the presence of tumor Ag-specific CD8⁺ T cells in the peripheral blood, metastatic melanoma often evades immune-mediated destruction. Even after therapeutic efforts to expand Ag-specific T-cell populations, the correlation between magnitude of response and clinical efficacy has been weak. Because the migratory phenotype of tumor Ag-specific effector T cells may determine their ability for tumor control, we hypothesized that the expression of CC or CXC chemokine receptor (CCR) molecules on activated CD8⁺ T cells may define phenotypes associated with more effective control of melanoma progression and prolonged survival. In a retrospective evaluation of patient isolates, CCR expression was determined for activated CD8⁺ T cells derived from the peripheral blood or tumor-involved lymph nodes of 52 patients with stage III or IV metastatic melanoma. In patients with stage III disease, expression of CXCR3 by CD8⁺CD45RO⁺ cells was significantly associated with enhanced survival. This was a stage-specific effect, because it was not observed in patients with stage IV disease. In addition, CCR4 and CXCR3 were highly coexpressed and associated with enhanced survival in stage III patients; however, CXCR3 seems to be the dominant receptor associated with clinical outcome. These findings support the hypothesis that the host immune system affects cancer progression and control, and that measures of CCR status of circulating lymphocytes may have prognostic value.