Background: The predictive value of dynamic changes in the expression of programmed cell death-1 (PD-1) among circulating CD8⁺ T lymphocytes for treatment response to PD-1 inhibitors has not been explored in non-small-cell lung cancer (NSCLC). This study aimed to investigate whether dynamic changes in PD-1⁺CD8⁺ T lymphocytes have predictive value with respect to durable clinical benefit (DCB) and survival after PD-1 blockade. Methods: Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled between March 2016 and August 2018 (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8⁺ T lymphocytes was conducted using multi-color flow cytometry. Predictive values of dynamic changes in circulating PD-1⁺CD8⁺ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with PD-1 inhibitor (NCT03486119). Results: Circulating PD-1⁺CD8⁺ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1⁺ cells among CD8⁺ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in analysis of tumor antigen NY-ESO-1-specific CD8⁺ T lymphocytes and in the validation cohort. Conclusions: Dynamic changes in circulating PD-1⁺CD8⁺ T lymphocytes predict clinical and survival benefit from PD-1 blockade treatment in NSCLC. Thus, tracking these changes may be useful for identifying NSCLC patients who will optimally benefit from the treatment.