Our understanding of how checkpoint inhibitors (CPIs) affect T cell evolution is incomplete, limiting our ability to achieve full clinical benefit from these drugs. Here, we analyzed peripheral T cell populations after one cycle of CPI treatment and identified a dynamic awakening of the immune system, as revealed by T cell evolution in response to treatment. We sequenced T cell receptors in plasma cell-free DNA and peripheral blood mononuclear cells and performed phenotypic analysis of peripheral T cell subsets from patients with metastatic melanoma treated with CPIs. We found that early peripheral T cell turnover and T cell receptor repertoire dynamics identified which patients would respond to treatment. Additionally, the expansion of a subset of immune effector peripheral T cells we call T_IE cells correlated with response. These events are prognostic and occur within 3 weeks of starting immunotherapy, raising the potential for monitoring patients’ responses by using minimally invasive liquid biopsies.