Among the treatments that patients with metastatic colorectal cancer (mCRC) commonly receive as first-line therapy, mFOLFOX6 (5-fluorouracil, leucovorin (folinic acid) and oxaliplatin) and CapeOX (capecitabine and oxaliplatin) are associated with a high incidence of toxicities. A phase III trial was conducted to assess the non-inferiority of first-line oral fluoropyrimidine S-1 and irinotecan compared with mFOLFOX6 or CapeOX in terms of progression-free survival (PFS): 243 patients received mFOLFOX6 or CapeOX plus bevacizumab (control group) and 241 patients received S-1, irinotecan and bevacizumab (experimental group). The median PFS duration was longer in the experimental group versus the control group (14.0 months versus 10.8 months). The incidence of adverse events of grade ≥3 was 58.6% and 64.9% respectively. Thus, the S-1 and irinotecan regimen was deemed non-inferior to standard first-line therapies for mCRC and could become a new standard treatment option.