High-dose IL-2 (HDIL-2) is associated with complete and durable responses in only 5–10% of patients with stage intravenous melanoma and the toxicity profile is significant. In-vivo human models have recently shown a stimulatory effect of exogenous IL-2 on both the Th17 and regulatory T-cell (TREG) compartments. We investigated and compared the effect of HDIL-2 on the Th17 and TREG compartments in HDIL-2 responders versus nonresponders. HDIL-2 was administered at a dose of 720 000 IU/kg to patients with melanoma (n=6) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 h during treatment. Peripheral blood mononuclear cells were isolated and subjected to intracellular cytokine and extracellular receptor staining for flow cytometry. Five of six patients progressed clinically on HDIL-2 therapy, and these patients showed an increase in the frequency of TREGs on day 4 of treatment. A single patient responded to HDIL-2 therapy and showed a decrease in the frequency of TREG cells on day 4 of treatment. We found that HDIL-2 resulted in a larger increase in the frequency and total numbers of IFNγ+Th17 cells in the complete responder compared with all nonresponders. As such, the complete responder showed a high IFNγ+Th17 : TREG ratio. Our results suggest that a distinct immunophenotype may be associated with response to HDIL-2. The peripheral IFNγ+Th17 : TREG ratio may serve as an early biomarker in the setting of HDIL-2 to help identify those patients who would benefit from subsequent cycles.