Background: Circulating tumor DNA (ctDNA) can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). Although patients with MRD positive status have extremely high risk of relapse, no standard treatment has been established for these patients after adjuvant chemotherapy. Trifluridine/tipiracil hydrochloride (FTD/TPI) is an oral anti-tumor agent combining thymidine-based nucleoside analogue with a thymidine phosphorylase inhibitor, which presents improved survival in patients with metastatic CRC refractory to fluoropyrimidines. Methods: The ALTAIR trial is a randomized, double-blind, phase III study designed to establish the superiority of FTD/TPI as compared with placebo in patients with resected CRC who show MRD positive status at any time after curative resection. ctDNA testing for screening patients with MRD positive is performed in the observational GALAXY study (UMIN000039205) that is a prospectively conducted large-scale nationwide registry designed to monitor ctDNA status for patient who can undergo curative resection. A personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) is used for the detection and quantification of ctDNA-based postsurgical MRD. Key eligibility criteria are (a) having undergone radical resection of primary and/or metastatic tumors, (b) a history of standard adjuvant chemotherapy, (c) positive ctDNA status within the previous 3 months at any time postoperatively, and (d) no obvious relapse confirmed by chest, abdominal, and pelvic CT scans. Patients will be randomly assigned in a 1:1 ratio to receive either 6 months of oral FTD/TPI or a matching course of placebo. Randomization is stratified by age (<70 vs. ≥70 years), stage (stage II or lower vs stage III vs. stage IV or M1), primary tumor location (right-sided vs left-sided colon vs rectum), ctDNA status at 1 month (positive vs negative or unmeasurable), and institution. The primary endpoint is disease free survival (DFS). Key secondary endpoints include rate of conversion from positive to negative ctDNA status, overall survival, adverse events, and quality of life. Assuming that the median DFS in the placebo group is approximately 8 months, a total of 240 patients (120 per arm) will provide 80% power to detect an expected DFS hazard ratio of 0.667 at two-sided significance level of 0.05, with an enrollment period of 2 years and a follow-up period of 1 year. This trial is actively accruing across 39 institutions in Japan and Taiwan and opened to recruitment in August 2018. By October 2021, a total of 67 patients have been enrolled. Clinical trial information: JapicCTI-205363/NCT04457297.