Background: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the esophagus and junction (AEG). The MAGIC and CROSS regimens were superior to surgery only in randomized controlled trials (RCTs) that included AEG but were not powered on this cohort, and no completed RCT has directly compared neoadjuvant chemotherapy and chemoradiation. This trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these Level I regimens. Methods: This open label, phase III RCT randomizes patients in a 1:1 fashion to receive either pre and postoperative chemotherapy as per the MAGIC regimen [Etoposide, Cisplatin, Fluorouracil (Capecitabine)] or neoadjuvant chemoradiation as per the CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 15% difference in 3 year overall survival, power at 80%, two-sided alpha level of 0.05, requiring 366 subjects over a five year period, with analysis performed one year after last subject recruited. Eligibility includes: AEG, types I, II, and III, staged (CT-PET and EUS) as cT2-3, N0-3, M0 and surgically resectable, with good performance status and no major co-morbidities. The primary endpoint is overall survival, with a minimum 3 year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumor regression grade, operative in-hospital complications, and health-related quality of life. Pre-treatment bio-resourcing of tumor and blood will enable correlative translational studies. Conduct to Date: The trial activated in February 2013 at the national center in Ireland, 35 patients are randomized to date. Other centers in Ireland and Europe will commence in 2014. Clinical trial information: NCT01726452.