Background: We previously reported that S-1 chemotherapy for gastrointestinal cancer (GI cancer) induced the high incidence of eye disorders (EDs), regardless of primary cancer site, treatment regimen and administration schedule (Yagisawa M, et al. 2017 Gastrointestinal Cancers Symposium). However, because this report showed a retrospective data from single institutional small cohort by reviewing medical records, we might have underestimated the incidence of EDs. So, we have conducted this prospective cohort study to confirm the incidence of EDs induced by S-1 more precisely. Trial design: This is a multicenter prospective cohort study to evaluate the incidence of EDs and ophthalmologic changes in GI cancer patients received S-1 chemotherapy. The key eligibility criteria are as follows: 1) Histologically confirmed carcinoma in GI cancer, including esophageal, gastric, colorectal, pancreatic, and biliary tract cancer.; 2) The patient who receives chemotherapy including S-1.; 3) No prior medication of S-1.; 4) No lachrymal duct obstruction and less than three points of corner conjunctiva epithelium disorder score. All participants receive four times of ophthalmological examinations. The primary endpoint is cumulative incidence of epiphora in periods from start of S-1 chemotherapy to 12 weeks after induction S-1. The secondary endpoints are cumulative incidence of epiphora in overall S-1 chemotherapy periods, the time of onset and severity of epiphora, the situation of ophthalmological intervention, ophthalmological changes, risk factors of epiphora, and QOL. Because we supposed that incidence of epiphora at 12 weeks after induction S-1 is 10% as already reported, we calculated the sample size as 160 based on precision of the 95% confidence interval and aimed to recruit 180 patients considering the possibility of 10% dropouts. This study is sponsored by Non Profit Organization Hokkaido Gastrointestinal Cancer Study Group. Clinical trial identification: UMIN 000027192 24, June, 2017 Legal entity responsible for the study: Hokkaido Gastrointestinal Cancer Study Group Funding: None Disclosure: S. Yuki: Honoraria: Taiho Pharmaceutical Y. Sakata: Consultant fee from Taiho Pharmaceutical Co., Ltd., Y. Komatsu: Grants for research and donations: Taiho Pharmaceutical Co., Ltd., All other authors have declared no conflicts of interest.