Accumulating evidence indicates that CD8 T cells in the tumor microenvironment and systemic CD4 T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non-small lung cancer and found that responders had significantly ( < 0.0001) higher percentages of effector, CD62L CD4 T cells prior to PD-1 blockade. Conversely, the percentage of CD25FOXP3 CD4 T cells was significantly ( = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62L CD4 T cells and CD25FOXP3 cells to predict nonresponders. Mass cytometry analysis revealed that the CD62L CD4 T-cell subset expressed T-bet, CD27, FOXP3, and CXCR3, indicative of a Th1 subpopulation. CD62L CD4 T cells significantly correlated with effector CD8 T cells ( = 0.0091) and with PD-1 expression on effector CD8 T cells ( = 0.0015). Gene expression analysis revealed that , and were preferentially expressed in CD62L CD4 T cells derived from responders. Notably, long-term responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62L CD4 T cells prior to PD-1 blockade therapy. Decreased CD62L CD4 T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62L CD4 T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4 T-cell immune statuses in their peripheral blood.