Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathological complete response to nCT, which correlates with increased 5-year survival compared to non-responders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies. Here, we investigated the immune mechanisms involved in nCT response by multi-dimensional profiling of pre-treatment tumor biopsies and blood from 68 EAC patients (34 prospectively and 34 retrospectively collected), comparing complete responders versus non-responders to nCT. At the tumor level, complete response to nCT was associated with molecular signatures of immune response and proliferation, increased putative anti-tumor tissue-resident memory CD39+CD103+CD8+ T cells and reduced immunosuppressive T regulatory cells and M2-like macrophages. Systemically, complete responders showed higher frequencies of immunostimulatory CD14+CD11c+HLA-DRhigh cells and reduced PDL1+ monocytic myeloid-derived suppressor cells, along with high plasma GM-CSF (pro-inflammatory) and low IL-4, CXCL10, C3a, and C5a (suppressive). Plasma pro-inflammatory and suppressive cytokines correlated directly and inversely, respectively, with the frequency of tumor-infiltrating CD39+CD103+CD8+ T cells. These results suggest that pre-existing immunity in baseline tumors drives the clinical activity of nCT in locally advanced EAC. Furthermore, it may be possible to stratify patients based on predictive immune signatures, enabling tailored neoadjuvant and/or adjuvant regimens.