T cells are an important effector cell population required for protective immunity against infectious diseases and cancer. Programmed cell death-1 (PD-1) serves as a crucial negative regulator of T cells, and contributes to tumor escape from immune surveillance. PD-L1 is expressed by both tumor cells and immune cells in the tumor micro-environment. In contrast the function of PD-L2, in tumor immunity is less clear. We previously showed that administering a novel multimeric form of soluble PD-L2 protein (sPD-L2) to mice infected with lethal malaria preventing loss of T cell functions mediated by PD-1, by inhibiting PD-1-PD-L1 binding, thus conferred long-term protection and was relevant to human disease (1). To better understand the contribution of PD-L2 to tumor immunity, we investigated the effect of sPD-L2 on melanoma growth in mice. In our study, we used the B16-F10 melanoma and the B16-F0 lung metastatic model. B16-F10 melanomas, injected intra-dermally on the back of each recipient mouse and treatments commenced on day 3, sPD-L2 treated mice controlled tumor size compared to the control group. Similarly, treatments commenced on day 9 slowed tumour progression by day 11 compared to the isotype control group. Thus, sPD-L2 reduced the progression of B16 melanoma when given either early or later after tumor progression. Also compared to anti-PD-1 treatment, mice treated with sPD-L2 had smaller tumor sizes. To determine if sPD-L2 had the potential to control metastatic tumours, an experimental metastasis model where mice were intravenously injected with B16-F0 luciferase-tagged melanoma cells. sPD-L2 treatment reduced the number and size of tumours measurable by bioluminescence. Overall we validated the ability of sPD-L2 as potential treatment for melanoma, where T cell immunity is ineffective or short-lived due to PD-1.