Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer. •CD39+ CD8+ T cells express features of exhaustion and tumor reactivity•CD39 expression enriches for CD8+ TCRs with tumor reactivity•CD39 expression on CD8+ T cells is non-redundant to tumor-based biomarkers•CD39+ CD8+ T cells are predictive of benefit from ICB Factors predicting benefit of immune checkpoint blockade (ICB) are needed. Here, Chow et al. demonstrate that CD39 expression marks tumor-reactive CD8+ T cells. High baseline levels of CD39+ CD8+ T cells are associated with ICB efficacy in lung cancer. Thus, CD39 is a potential tumor-extrinsic biomarker for guiding cancer management.