Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1⁺CD8⁺ T cells relative to that of PD-1⁺ regulatory T (T_reg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8⁺ T cells and T_reg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1⁺CD8⁺ T cells and enhanced PD-1⁺ T_reg cell–mediated immunosuppression. A profound reactivation of effector PD-1⁺CD8⁺ T cells rather than PD-1⁺ T_reg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.