A 46-year-old Japanese female with advanced gastric cancer with positive peritoneal cytology and who was refractory to methotrexate plus 5-FU sequential chemotherapy received low-dose, fractional irinotecan hydrochloride (CPT-11) in combination with cisplatin. This regimen could be repeated biweekly on an outpatient basis and was well tolerated. After 8 cycles of administration, a negative change in peritoneal cytology subsequently enabled a total gastrectomy, splenectomy, and cholecystectomy with a D3 lymph node dissection. The rationale for a low-dose, fractional administration of CPT-11 in combination with cisplatin is the synergistic antitumor activity obtained through the ability of SN-38 to potentiate cisplatin-induced cytotoxicity, as well as the increased therapeutic efficacy of a protracted CPT-11 administration over more intense treatment schedules. As far as we are aware, this case report demonstrates for the first time that a low-dose, fractional administration of CPT-11 with cisplatin can successfully produce a negative change in peritoneal lavage cytology, and potentiates a R0 resection in a 5-FU resistant advanced gastric cancer patient. This suggests that this combination could be an effective regimen for potentially disseminated, 5-FU resistant patients.