Abstract Background We conducted a prospective randomized study of an adjuvant oxaliplatin-based regimen plus orally administered tegafur-uracil in patients with stage III colon cancer after radical resection to evaluate the feasibility of this drug combination in cancer clinical outcomes, acute toxicity, disease-free survival (DFS), and overall survival (OS) in Taiwan. Methods/design This is an open-label, randomized, comparative, double-arm, multicenter, phase III study to assess DFS, OS, and safety profiles of the aforementioned drug combination as maintenance therapy for 1Â year in patients with stage III colon cancer after radical resection in Taiwan. Following the completion of an adjuvant oxaliplatin-based regimen for 3Â weeks with no evident disease recurrence, all eligible patients will be randomly assigned to either arm A (maintenance therapy) or arm B (observation arm) in a 2:1 ratio (364 and 182 patients in the tegafur-uracil and observation groups, respectively). Treatment in arm A will be started within 7Â days of randomization. If the patients reported disease recurrence, intolerable toxicity, withdrew consent or the investigator determined that the patient should be withdrawn during the study period, they were withdrawn from the study. If a patient was discontinued from the study, the corresponding data were not reused, and the patient was not allowed to re-enter the study. Discussion A unique characteristic of this intervention was that the adjuvant chemotherapy with oxaliplatin and tegafur-uracil was anticipated to be safe and has high treatment efficacy, with the advantage of yielding a favorable response rate and tolerable toxicity profile. Trial registration ClinicalTrials.gov, identifier: NCT02836977 . Registered on 18 July 2016.