BACKGROUND: The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX. METHODS: Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity. RESULTS: A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3-16.0), the median OS was 45.4 months (95% CI 37.4-NA), and the RR was 56.0% (95% CI 42.3-68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%). CONCLUSIONS: First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.