Background: There was no consensus about the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective cohort study of patients with stage III CRC aged ≥80 years who underwent curative resection together with a phase II feasibility study on uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy. Methods: This multi-institutional prospective cohort study involved 17 institutions in Hiroshima, Japan. Patients with stage III CRC aged ≥80 years who underwent curative resection were enrolled. We prospectively collected the clinicopathological data including the status of the administration of adjuvant chemotherapy, follow-up, and oncological outcomes. The primary endpoint was three-year disease-free survival (DFS) and secondary endpoints were three-year overall survival (OS) and relapse-free survival (RFS). Results: From December 2013 to June 2021, 214 patients were examined. There were 99 men and 115 women with the median age of 84 years (range, 80–101). There were stage IIIA diseases in 27 cases, IIIB in 158 cases, and IIIC in 29 cases (TNM eighth edition). Median follow-up time was 42.5 months (range, 0.16–84.04 months). Thirty-six patients died due to CRC and 30 patients died due to other causes. There was recurrence in 58 cases (27.1%), and any treatment was administrated in 29 patients. Secondary cancers were observed in 17 cases in the follow-up period. The three-year DFS was 63.6%, 3-year OS was 76.9%, and 3-year RFS was 63.1%. Adjuvant chemotherapy was administrated in 64 cases and the completion rate was 53%. Adjuvant chemotherapy tends not to be given in older age, poor performance status, high Charlson comorbidity index, and low preoperative prognostic nutritional index. In a study of 80 patients adjusted for background factors using propensity score matching, it was shown that patients who completed planned treatment have improved DFS. Conclusions: Completion of adjuvant chemotherapy may improve prognosis in CRC patients over 80 years of age, but the number of patients who would benefit was limited. Appropriate dose adjustment and supportive care for postoperative adjuvant chemotherapy are important, as well as the need to identify patient groups who will not tolerate chemotherapy.