Tumor cells use various methods of immunosuppression to overcome antitumor immunity. One such method is that of programmed death ligand-1 (PD-L1 or B7-H1), which upon binding its receptor PD-1 on T cells triggers apoptotic death of the activated T cells. Overexpression of the costimulatory molecule CD80 on PD-L1⁺ tumor cells, or inclusion of a soluble form of CD80 (CD80-Fc), maintains the activation of PD-1⁺–activated T cells. Using T cells from CD28-deficient mice and antibodies to block CD28 on human T cells, we now report that a soluble form of CD80 mediates this effect by simultaneously neutralizing PD-1–PD-L1-mediated immunosuppression and by providing CD80–CD28 costimulation, and is more effective than antibodies to PD-L1 or PD-1 in maintaining IFNγ production by PD-1⁺ activated T cells. Therefore, soluble CD80 may be a more effective therapeutic than these checkpoint antibodies for facilitating the development and maintenance of antitumor immunity because it has the dual functions of preventing PD-L1–mediated immunosuppression and simultaneously delivering the second signal for T-cell activation. Cancer Immunol Res; 2(7); 610–5. ©2014 AACR.