OBJECTIVE To compare a bi-weekly infusion of leucovorin (LV) 5-fluorouracil (5-FU) for 2 days, plus oxaliplatin (LV5- FU2-oxaliplatin) and LV5-FU2-cisplatin (CDDP) regimens with respect to toxicity, objective response rates, time to progression (TTP) and overall survival (OS) in patients with advanced gastric cancer. METHODS Patients received LV5-FU2- oxaliplatin (oxaliplatin 85 mg/m(2), day 1; folinic acid 200 mg/m(2), days 1-2; 5-FU 400 mg/m(2), i.v. bolus, days 1-2; 5-FU 600 mg/m(2), 22-hour continuous infusion, days 1-2) or LV5- FU2-CDDP (CDDP 50 mg/m(2), day 1; plus LV5-FU2). A total of 72 patients were enrolled into this study (36 vs. 36). RESULTS A total of 305 cycles were administered in the LV5-FU2-oxaliplatin arm (median 8) and 272 cycles in the LV5-FU2-CDDP arm (median 8). Grades 3-4 toxicity were as follows (LV5-FU2-oxaliplatin %/LV5-FU2-CDDP %; p<0.05): neutropenia 5/49, thrombocytopenia 2/6, anemia 6/16 nausea/vomiting 2/15, and mucositis 0/3. Response rate of LV5-FU2-oxaliplatin was 41% (partial response/PR 41%, stable disease/SD 31%, progressive disease/PD 28%; 95% confidence internal/95% CI 27-58) and of LV5-FU2-CDDP was 25% (PR 25%, SD 36%, PD 39%; 95% CI 14-41; p =0.013). The median TTP of the patients in the LV5-FU2-oxaliplatin arm was 8 months and 6 months for those in the LV5- FU2-CDDP arm (p=0.073). The median survival time of the patients in the LV5-FU2-oxaliplatin arm was 10 months and 7 months for those in the LV5-FU2-CDDP arm (p=0.003). CONCLUSIONS Our study showed that oxaliplatin may be substituted for cisplatin with LV5-FU2 with favorable safety and efficacy profile. The encouraging results from our study support the effectiveness of oxaliplatin-fluoropyrimidine- containing chemotherapy in gastric cancer and could provide a new core on which to add other agents in future investigations.