The A_2b receptor (A_2bR) belongs to the adenosine receptor family. Emerging evidence suggest that A_2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A_2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A_2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1) and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b⁺Gr1⁺) myeloid-derived suppressor cells (MDSCs). Depletion of CD11b⁺Gr1⁺ cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A_2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b⁺Gr1⁺ cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8⁺) T cells and natural killer T (NKT) cells and increased levels of T helper 1 (Th1)-like cytokines. Adoptive transfer of CD11b⁺Gr1⁺ cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A_2bR antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma.