Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ type II and III (≥ cT2 or cN+) were enrolled. Pts were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) alone (Arm A) or the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, overall survival (OS), disease-free survival (DFS) and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 152 pts were analyzed within the intention to treat population. Baseline characteristics were similar between arms (male, 70%; median age, 60y; cT3/T4, 82%; cN+, 77%; GEJ, 45%). The rate of cancers with signet-ring cell component was at 45%. The FLOT-RAM arm included more unfavorable pts with T4 (8% vs. 5%), impaired ECOG PS of 1 (32% vs. 20%), and concomitant disease (86% vs. 76%). 92% of pts with FLOT as well as with FLOT-RAM completed the 4 pre- cycles. R0-resection could be achieved in 82% of pts with FLOT and 96% of pts with FLOT-RAM (p = 0.0093). The rate of major path response was similar in both arms and was 29% for FLOT and 26% for FLOT-RAM. Median DFS was slightly improved in pts with FLOT-RAM (32 months vs. 21 months), while median OS was similar in both treatment arms (FLOT 45 months, FLOT-RAM 46 months). Surgical morbidity was observed in 32% of pts with FLOT and 41% of pts with FLOT-RAM. Mortality at 60 days after surgery was 4.1% with FLOT and 2.8% with FLOT-RAM. There were bit more G≥3 adverse events with FLOT-RAM (76% vs. 92%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates and slightly prolonged DFS without an impact on path response or overall survival. FLOT-RAM is feasible and safe, when type I tumors are excluded. Clinical trial information: NCT02661971.