Background: Adjuvant chemotherapy with tegafur/uracil(UFT)used to be a tentative Japanese standard treatment and has been replaced by S-1 according to the result of the ACTS-GC trial,although there has been no direct comparison.Paclitaxel(PTX)has been widely used as one of the key drugs for unresectable GC.A randomized phase Ⅲ trial with a two-by-two factorial design was planned to assess the survival benefit of sequential use of PTX and oral fluorinated pyrimidines(FPs)in comparison with FPs alone,and to compare UFT and S-1.Methods: Patients with serosa-invading GC who underwent R0/1 resection with extended(D2)lymph node dissection were randomized to receive either UFT 267mg/m2 daily(arm A),S-1 80mg/m2 daily for 2 weeks every 3 weeks(B),weekly PTX 80 mg/m2 followed by UFT(C),or PTX followed by S-1(D)for 24 weeks.The primary endpoint was disease-free survival(DFS).708 patients per groups were necessary to detect a hazard ratio of 0.8 with 90%power for superiority of the sequential arms,C+D,vs.A+B(two-sided 5.0%significance level).The number of patients was set to 370 per arm(total 1480)with an 88%power for noninferiority(1.33 as the margin)of UFT vs.S-1.Results: Between August 2004 and October 2007,1,495 patients from 232 centers were randomized with the full analysis set of 1,433.Demographics were well balanced among arm A(n=359),B(n=364),C(n=355),and D(n=355); mean age was 64,86%were PS 0,68%of tumors were 8 cm or greater and 85%were clinically node positive.Grade 3-4 neutropenia or anorexia occurred in 11%or 6%,13%or 7%,13%or 2%,and 23%or 5%for arm A,B,C,and D,respectively.Other%grade 3-4 toxicities were less than 5%.Median follow-up was 1,875 days and 728 events occurred.Difference in DFS between C+D and A+B were not statistically significant(HR=0.92,95%CI 0.80-1.07,p= 0.273).HR of A+C vs.B+D was 1.23(95%CI 1.07-1.43)and hence the null hypothesis was not rejected.Conclusions: There was a trend for better DFS for sequential use of PTX followed by FPs.Comparison between the FPs demonstrated that UFT was inferior to S-1.Sequential PTX/S-1 is safe and effective for locally advanced GC in an adjuvant setting.