Significance Despite the success of checkpoint-targeting therapies, many melanoma patients do not respond or acquire resistance after initial responsiveness. A better understanding about the mechanism by which these therapies enhance immune-mediated tumor control is key to providing the rationale for better treatment strategies. In this study, we show that PD-1 blockade does not modulate the breadth or the magnitude of the circulating tumor-reactive CD8 T cell response. In contrast and in concordance with our previous study, CTLA-4 blockade leads to a broadening of the circulating melanoma-reactive CD8 T cell response. Together, these findings show differential mechanisms of action of CTLA-4 and PD-1 blockade and support the synergy of the combination treatment seen in the clinic.