Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1(-/-)) or control (SOCS1(+/+)) mice on an IFN-γ(-/-) C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1(+/+) mice receiving IFN-A/D had significantly enhanced survival versus PBS-treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1(-/-) mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1(-/-) mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8(+) T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1(-/-) mice as compared with mice receiving a control antibody (P = 0.0021). CD4(+) T-cell depletion from SOCS1(-/-) mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1(+/+) or SOCS1(-/-) mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1(+/+) or SOCS1(-/-) mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor effects of IFN-α in the setting of melanoma.