The effects of a novel oral fluoropyrimidine derivative S-1 on peritoneal metastasis from gastric cancer were investigated. OCUM-2MD3 cells, a highly peritoneal-metastatic cell line, were injected intraperitoneally in nude mice. These mice were allocated to the following three groups (each group, n=10): the S-1 group, to which 10 mg/kg body weight of S-1 was administered per os daily; the FT group, to which 100 mg/kg body weight of tegafur (FT) was administered per os daily; the control group, to which no anticancer drug was administered. Drug administration was starting the day after inoculation. The median survival time of the S-1 group was found to be significantly longer than that of the FT group (30 days vs. 23 days; P<0.005) and the control group (vs. 24 days; P<0.005). The mean values of 5-fluorouracil (5-FU) concentrations in ascites of the S-1 group at 1-4 h were 414-580 ng/ml (n=5), and those of FT group were 70-87 ng/ml (n=5), with significant differences between the two groups at each observation time. The high CDHP concentrations in ascites of the S-1 group were observed at 1-6 h after drug administration. DPD was expressed strongly in fibrous tissue around peritoneal metastasis and weakly in tumor cells of peritoneal metastasis themselves. The high concentrations and long duration of 5-FU in the peritoneal cavity after S-1 administration suggest that S-1 may be effective against peritoneal dissemination. High concentrations of CDHP may prevent 5-FU degradation in peritoneal dissemination and its surrounding fibrous tissue.