Chemokines play an important role in regulating tumor-mediated immunity, angiogenesis, and tumor cell metastasis. The chemokine receptor, CXCR3, is expressed in various human tumors, including renal cell carcinoma (RCC). CXCR3 is also associated with antiangiogenic effects in multiple tumors, and we hypothesized that interleukin-2 (IL-2) treatment of patients with metastatic clear cell RCC could augment CXCR3 levels on circulating mononuclear cells and correlate to outcome. The kinetics of CXCR3 expression on circulating mononuclear cells and its ligands (CXCL9, CXCL10, and CXCL11) in plasma were evaluated in 20 patients with metastatic clear cell RCC during cycles 1 and 2 of high dose IL-2 therapy. Subpopulations of peripheral blood mononuclear cells (PBMCs) were studied by dual color flow cytometry. Angiogenic ligands were measured and an "angiogenic ratio" was calculated prehigh and posthigh dose IL-2. CXCR3 expression on PBMC at baseline was similar in patients with metastatic RCC and normal controls. PBMC CXCR3 expression increased during treatment, and peaked during cycle 2. Plasma from RCC patients displayed similar baseline levels of CXCR3 ligands to normal controls. However, the angiogenic ratio was significantly increased in patients with metastatic RCC at baseline. Plasma levels of CXCR3 ligands increased during treatment, resulting in a reversal in the angiogenic ratio to favor angiostatic chemokines. The CXCR3/CXCR3 ligand biologic axis and angiogenic ratio may be important biomarkers in clear cell RCC patients who are undergoing high dose IL-2 therapy.