Background: T cell exhaustion represents a distinct T cell differentiation state following antigen encounter. Exhausted T cells that arise during cancer progression sustainably express PD-1; blockade of PD-1/PD-L1 immune checkpoint thus has had startling success in human melanoma. Nevertheless, durable clinical benefit of PD-1/PD-L1 blockade is still not achieved in most patients. Recent reports indicated that reinvigoration of exhausted T cells in mice by PD-L1 blockade was transient, and reinvigorated T cells became re-exhausted if antigen concentration remained high. Here we investigated whether IL-2 treatment sustains the PD-L1 blockade‒mediated reinvigoration of T cell function in melanoma. Methods: B16-F10 inoculated B6 mice were adoptively transferred with 2 million activated Pmel-1 cells (48 hours after in vitro stimulation with gp100_25–33) on day 3, and injected i.p. with 400 μg anti-PD-L1 (clone 10F.9G2) on days 3, 6, 9 and with 5 μg human IL-2 b.i.d. until a tumor size of 1000 mm³was reached. Tumor progression was determined and tumor infiltrating T cells were analyzed by flow cytometry. Results: In B16-F10 inoculated mice with or without Pmel-1 cell transfer, anti-PD-L1 plus IL-2 more potently inhibited tumor progression than did anti-PD-L1 or IL-2 alone. In B16-F10 inoculated mice transferred with Pmel-1 cells, majority of infiltrating Pmel-1 cells in B16 melanoma lost IFN-γ production within 20 days post initial PD-L1 blockade alone (only 8-25% infiltrating Pmel-1 cell expressed IFN-γ). By contrast, at 20 days post initial PD-L1 blockade plus IL-2 treatment, 40-50% Pmel-1 cells infiltrating in melanoma produced IFN-γ, an indication of T cell function. Conclusions: IL-2 treatment sustains the PD-L1 blockade‒mediated reinvigoration of T cell function in melanoma. These findings may have important clinical implications for patients with melanoma.