Background: Up to 40% of GC patients show synchronous PC at time of diagnosis and peritoneal relapse develops in 10–46% of cases after radical surgery. Systemic chemotherapy is standard method of treatment with median survival of several months. Innovative therapeutic approaches are needed to improve survival. Methods:Phase-2, open label prospective clinical trial assessing safety and efficacy of bidirectional chemotherapy for treating of gastric cancer with PC. Treatment protocol for untreated patients included initial staging laparoscopy or laparotomy, 3–4 courses of systemic chemotherapy (XELOX) followed by Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) procedures every 6 weeks until progression of disease or death. Criteria of progression included 50% and more PCI increase or distant metastases. Patients with primary or recurrent GC, who received earlier one or two lines of systemic chemotherapy, didn’t receive 4 XELOX courses before PIPAC. Primary endpoints were overall survival and histological peritoneal regression grading score after rebiopsy. Results:46 patients were included (14 men, 32 women, mean age 53.5 years), 33 patients had primary GC with PM and 13 had peritoneal relapse after surgery. 15 patients had systemic chemotherapy before inclusion to the program. About one half of patients had ascites. Mean PCI was 12.1 (min-max 3-34). Altogether, 89 PIPAC procedures were performed in the 46 patients. Complete and partial pathological response was found in 91% of the 23 patients eligible for tumor response assessment (7 and 14 patients, respectively). Median survival was 14 months and one-year overall survival was 55%. The median survival was better in patients with low PCI in compare with high PCI, but the difference was not significant. Conclusions: Bidirectional chemotherapy combining XELOX with PIPAC with cisplatin and doxorubicin can induce objective tumor regression and is associated with a promising survival in GC with PC.