Background: Optimal neoadjuvant (NA) treatment for adenocarcinoma of the esophagus and esophagogastric junction is unknown. This study aims to evaluate an approach of offering NA chemoradiotherapy (CRT) to T3/T4 tumours with a threatened circumferential resection margin (CRM) on staging imaging (computerized tomography/endoscopic ultrasound/positron emission tomography) and NA chemotherapy (CT) to T3/T4 tumours with a non-threatened CRM. Methods: Cases with clinically staged T3/T4 tumours who underwent a radical esophagectomy at a single tertiary referral centre between 2013 and 2019 were retrospectively reviewed. NA CRT was given as 41.4Gqy in 23 fractions with weekly carboplatin/paclitaxel and NA CT was given as a platinum based combination. Survival outcomes are described using the Kaplan-Meier method and calculated from NA treatment start. Results: 81 patients were identified - 18 (22%) received CRT and 63 (78%) received CT. More cases had Stage IVA disease in the CRT group (28% vs. 8%). CT consisted of a platinum/fluoropyrimidine doublet (43%), triplet with epirubicin (51%) or FLOT (6%). Median follow up was 68 months. Median length of post-operative stay (11 days for both) and rate of death within 90 days of surgery (6% vs. 3%) were similar. Rates of R0 resection (100% vs. 67%) and tumour regression grade 1/2 (55% vs. 14%) favoured CRT. There was no difference in overall survival (HR 0.92 (95%CI: 0.45-1.87), p=0.81). Estimated 3 year relapse-free survival was 39% (95%CI: 14-64) for CRT and 45% (95%CI: 33-58) for CT. Location of first relapse was local, distant or both in 0%, 75% and 25% for CRT and 6%, 50% and 44% for CT. In the CT group, overall survival was inferior for patients with an R1 resection (HR: 6.30 (95%CI 3–14), p<0.001). Conclusions: Neoadjuvant chemoradiotherapy for CRM-threatened cases of locally advanced adenocarcinoma of the esophagus and esophagogastric junction resulted in a very low rate of R1 resection and similar survival outcomes to non-CRM-threatened cases treated with neoadjuvant chemotherapy. Tailoring the neoadjuvant approach based on risk to CRM involvement appears feasible and warrants further investigation.