BACKGROUND: Tumor budding (TB) has been described as an adverse prognostic marker for operable colorectal cancer (CRC); however, a limited number of studies have demonstrated the prognostic significance of TB in patients with drug therapy. This study was conducted to determine the predictive power of TB in stage III CRC patients who received adjuvant chemotherapy. METHODS: We retrospectively collected clinicopathological data including TB of 237 stage III colorectal cancer patients at Hiroshima University Hospital between July 1, 2006 and June 31, 2019. Differential disease-free survival (DFS) was investigated according to TB status. RESULTS: This study included 237 patients with a median age of 67 years, comprising patients who underwent surgery alone (n = 65), 5-fluorouracil (5-FU) monotherapy (n = 129), and oxaliplatin-based chemotherapy (n = 43). Overall, 81 patients developed disease recurrence, and 33 patients died of cancer-related causes. The TB status was categorized into two groups: 99 with low budding (< 5 buds) and 138 with high budding (≥ 5 buds). Overall, the low budding cases demonstrated significantly better DFS. In the 5-FU monotherapy group, low-risk patients (T1, T2, or T3 and N1) with low budding showed a remarkably higher 3-year DFS (91%) compared to high budding (55%). CONCLUSION: Our results indicate that TB could play a subsidiary role in selecting patients who could maintain a favorable prognosis with 5-FU monotherapy in stage III CRC.