Background: The immunomodulatory effects of IL-12 are well known to result in potent anti-tumor responses. However its therapeutic development has been hindered by its potential toxicity. Here we explored the impact of systemic low dose IL-12 administration as a strategy to enhance the efficacy of PD-1 blockade. Methods: Mice bearing D4M melanoma tumors were treated with anti PD-1 antibody alone or in combination with low dose IL-12 (100ng twice a week). Tumor progression was monitored, and characterization of immune cell types was performed by flow cytometry and gene expression analysis. Results: A significant reduction in tumor progression after combinatorial treatment with low dose IL-12 and anti PD-1 was observed. This synergistic effect was associated with elevated levels of intratumoral IFN-γ, iNOS, CXCL9, CXCL10, CXCL11, and perforin. Single treatment with low dose IL-12 induced a decrease in the levels of circulating neutrophils and an increase in the levels of circulating CD8⁺ T cells. Within the TME, low dose IL-12 treatment was associated with an increase in the frequencies of tumor infiltrating M-MDSCs expressing high levels of CXCL9. Elevated levels of CD8⁺ TILs were also found, which were characterized by their increased expression of PD-1 and PD-L1, as well as CD107a, CXCR3 and CD103. No signs of toxicity were noted. Conclusions: Low dose IL-12 synergizes with anti PD-1 to induce superior regression of D4M melanoma tumors. This effect was associated with an increase in the levels of molecules involved in the recruitment and effector function of CD8⁺ T cells. Analysis of tissues from animals treated with low dose IL-12 alone showed significant changes in the composition and phenotype of myeloid and T cells in both the tumor and blood. Expression of CXCL9 on tumor infiltrating MDSCs suggested a reversal of their immunosuppressive function to an immunopromoting one, and could explain the elevated accumulation of CD8⁺ TILs via enhanced CXCR3-dependent recruitment. These findings suggest that low dose IL-12 is sufficient to induce changes in the TME, with minimal toxicity,that enhance the anti-tumor effects of PD-1 blockade. A clinical study testing the safety of this combination is currently underway.