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Background. Peritoneal dissemination is a common feature in patient with locally advanced gastric cancer. Syncronous peritoneal metastases are found in 10-20% of patients and during the follow-up a further 60% of patients with T4 stage develop peritoneal cancer with a rapid deterioration of survival rates. Systemic chemotherapy has little effect on peritoneal dissemination because the peritoneal-blood barrier hinders drug distribution throughout the peritoneal cavity. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed for the treatment of peritoneal dissemination, thought the biological effects of this treatment are largely unexplored. Aims. To investigate the effects of HIPEC on an experimental murine model of peritoneal carcinomatosis. Materials and Methods. MKN45 cells lines were injected into the peritoneal cavity of NOD-SCID mice. Mice were randomized as follow: HIPEC plus mytomycine (16,5 mg/L of perfusate each mouse) and cisplatin (125 mg/L of perfusate each mouse), normothermic intraperitoneal chemotherapy (NIPEC), normothermic intraperitoneal saline (NIPES) and hyperthermic intraperitoneal saline (HIS); and control group. After 8 days from the intraperitoneal injection mice were sacrificed and the extent of peritoneal carcinogenesis was evaluated. All peritoneal and mesenteric nodules were examined, counted and measured. Results. 100% of mice injected with MKN45 cells developed diffuse colonization of peritoneal cavity, HIPEC, effectively reduced the extent and severity of peritoneal dissemination as measured by assessing the total number of peritoneal nodules and mesenteric nodules as well as the total volume of peritoneal nodules. However, both HIPEC and NIPEC treatment were associated with a slight deterioration clinical parameters including weight loss. HIPEC treatment effectively downregulated the expression of genes involved in the formation of peritoneal cancer nodules. Thus by gene array we found that HIPEC caused a robust downregulation in CXC chemokine Receptor-4 (CXCR4); SMAD2, a family of proteins that mediate TGF-β signalling pathway; C-terminal binding protein (CTBP1); collagen IV (COL4A2); APC, a gene correlated with beta-catenin expression. HIPEC treatment ameliorates long-term survival (5 weeks) by 50% in comparison to control mice. Conclusions. HIPEC protects against peritoneal dissemination in a mouse model of peritoneal gastric cancer carcinogenesis with a positive citology. HIPEC might represent a prophylactic approach to patients with locally advanced gastric cancer at a high risk to develop peritoneal cacinomatosis. HIPEC acts at multiple check-points in the process of attachment and adhesion of tumor cells in the peritoneum.