Background: Taxanes have been standard regimen as the first-line chemotherapy for metastatic breast cancer. However side effects such as neutropenia, peripheral neuropathy, edema or alopecia are important concerns. Phase II clinical trials of TS-1, an oral 5-fluorouracil derivatives (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate), have shown good clinical efficacy and tolerability. Therefore, we conducted a phase III open-label randomized controlled trial (SELECT BC) to verify the non-inferiority of TS-1 in overall survival (OS) to taxane as first-line chemotherapy for metastatic breast cancer. Methods: Six hundred eighteen patients receiving first-line chemotherapy for metastatic breast cancer were randomly assigned to either taxane group (n=309) or TS-1 group (n=309). In the taxane group, patients received docetaxel 60-75mg/m2 q3w, paclitaxel 80-100mg/m2 q1w or paclitaxel 175 mg/m2 q3w at the discretion of the treating physician. In the TS-1 group, patients received TS-1 40–60 mg twice daily based on the patient’s body surface area for 28 days on, 14-day off. The primary endpoint was OS, with a non-inferiority margin of 1.333. Secondary endpoints were time to treatment failure (TTF), progression free survival, adverse events, health-related quality of life and cost-effectiveness. Results: After a median follow-up of 34.6 months, median OS was 37.2 months in the taxane group and 35.0 months in the TS-1 group (hazard ratio 1.05, 95% CI 0.86–1.27, p=0.015). Median TTF was 8.9 months in the taxane group and 8.0 months in the TS-1 group (hazard ratio 1.10, 95% CI 0.93–1.30, p=0.022). The incidences of diarrhea, mucositis and nausea were higher with TS-1, whereas the incidences of edema, peripheral neuropathy, arthralgia, allergic reaction, fatigue and alopecia were higher with taxanes. Utilities measured by EQ5D during treatment were similar (repeated measures ANOVA p=0.66) between two groups. Conclusions: SELECT BC clearly demonstrated that OS with TS-1 is not inferior to that with taxane in patients receiving first-line chemotherapy for metastatic breast cancer. TS-1 monotherapy would be one of the standard regimens for this patient population. Clinical trial information: C000000416.