After the ESOPEC trial showed a survival benefit for fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT)-treated adenocarcinomas of the esophagus (EAC) and the gastroesophageal junction (GEJ) compared with Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS), a European, high-volume center study for stage cT2cN0 EAC and GEJ was undertaken, as it has been published that a third of these patients are understaged and could benefit from a multimodal approach PATIENTS AND METHODS: Retrospective analysis of prospective databases from ten high-volume European centers was performed. Inclusion criteria were GEJ Siewert type I/II or EAC with cT2cN0 status at diagnosis undergoing multimodal treatment with FLOT or CROSS. Primary endpoint was overall survival (OS) RESULTS: Between 2012 and 2023, 133 patients met the inclusion criteria, of whom 73 (54.9%) received CROSS and 60 (45.1%) underwent treatment with FLOT. In both groups, patients were mainly male (p = 0.08), older than 70 years (p = 0.24), and had American Society of Anesthesiologists (ASA) II classification (p = 0.45). Regarding surgical treatment, more patients underwent gastrectomy in the FLOT than in the CROSS cohort (23.3% versus 6.8%, p = 0.007). There were no differences regarding pT, pN, and pM category (p > 0.05). Median survival was not reached, while mean survival was 74.6 months (95% CI 60.5-88.7 months) for CROSS versus 100.8 months (95% CI 72.5-94.5 months, p = 0.028) for FLOT. The 3-year survival was 87% in the FLOT group versus 59% in the CROSS group. In multivariable analyses, FLOT was independent factor for survival (p < 0.001) CONCLUSIONS: For cT2cN0 staged EAC and GEJ type I /II patients FLOT chemotherapy showed a survival benefit and should be the preferred treatment in a multimodal approach.