Background: Peritoneal relapse is seen in 60-70% of patients with diffuse type gastric cancer (gc), compared to 20-30% with intestinal type according to Laurens`s classification. Hyperthermic intraperitoneal chemoperfusion (HIPEC) is an increasingly used therapy method for patients (pts) with peritoneal metastases. The preventive use of HIPEC could represent an approach for diffuse type cell gc pts before macroscopic peritoneal seeding has evolved, since pts with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. Methods: This is a multicenter, randomized, controlled, open-label phase III study including a total of 200 pts with localized and locally advanced diffuse type cell adenocarcinoma of the stomach and type II/III gastroesophageal junction (i.e. ≥cT3 any N or any T N positive). A negative diagnostic laparoscopy before treatment and 3-6 pre-operative cycles of FLOT are a prerequisite for enrollment (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2wk). Pts were randomized 1:1 to receive surgery only and postoperative FLOT (Arm A-control arm) or surgery + intraoperative HIPEC (cisplatin 75mg/m² solution at 42°C for 90 min) and postoperative FLOT (Arm B-experimental arm). Surgery is carried out as subtotal, total gastrectomy or transhiatal extended gastrectomy. The scope of the trial is to evaluate the efficacy as well as the safety and tolerability of the combination of perioperative chemotherapy combined with an intraoperative prophylactic HIPEC. Here, we show safety results from the pre-specified safety analysis after 20 pts had undergone surgical resection plus HIPEC and the corresponding 20 pts in the control arm. Results: Treatment arms were balanced regarding age, ECOG and tumor parameters like localization of the primary, of lymph nodes or cTN stage. Most pts in both arms received a subtotal or total gastrectomy. In 15 out of 20 arm B pts the HIPEC was 6 pts (30%) in Arm A and 7 pts (35%) in Arm B were seen with at least one SAE. Perioperative complications resulted in overall 7 SAEs in Arm A and in 4 SAEs in Arm B. One postoperative mortality (grade 5) was documented in Arm B due to septic complication. 11 pts showed no complications in both arms according to Clavien-Dindo-Classification. 6 pts in Arm A and 2 in Arm B showed grade 3. No patient was grade 4. Conclusions: The incidence of perioperative morbidity with surgical and/or medical complications were nearly equal in both treatment groups. The safety data showed no abnormalities or evidence increase in toxicity-rates including postoperative complications or increased severity of documented events within the experimental HIPEC arm. Clinical trial information: NCT04447352.