Background Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC. Methods Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group. Results Overall, 129 (19%) of 689 patients included had SRCs (nCT: n  = 64; nCRT: n  = 65). The SRC group had a more advanced ypT stage ( p  = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range IQR) 2 0–5 vs. 1 0–3; p  = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p  = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median IQR 12 5–50 vs. 23 8–164; p  = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT. Conclusions SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS.