Adenocarcinoma of the esophagus and gastroesophageal junction is a common disease. This disease is significantly more prevalent in men, although the main underlying risk factor has an equal sex distribution. In locally advanced disease, multimodal therapy has been developed as the standard in the western world. Neoadjuvant chemoradiotherapy or perioperative chemotherapy using the FLOT regimen was established as the standard. Most recently, adjuvant immunotherapy after neoadjuvant chemoradiotherapy and surgery has been introduced into the multimodal therapy. Substantial sex-specific differences in outcome in multimodal therapy have been described in retrospective subgroup analysis. Further studies are warranted to dissect the sex-specific differences in these treatment regimens.