BACKGROUND: Subsequent lines of therapy for chemotherapy-resistant metastatic colorectal cancer (CRC) have shown limited efficacy. Herein, we retrospectively investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) using oxaliplatin plus 5-FU/FUDR in patients with unresectable colorectal liver metastases (CRLM) who progressed following standard chemotherapy regimens. METHODS: From March 2017 to April 2023, CRC patients with unresectable CRLM who progressed following standard chemotherapy and subsequently received HAIC oxaliplatin plus 5-FU/FUDR were evaluated. Objective response rate (ORR), disease control rate (DCR), median depth of tumor response (DpR), no evidence of disease (NED) rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. RESULTS: A total of 21 patients who progressed after a median of two (range: 1-4) lines of standard systemic chemotherapy were included. The ORR and DCR were 28.6 % and 95.2 %, respectively, with six patients reaching partial response. Additionally, the median DpR was 10.6 %, and seven patients underwent successful conversion surgery. Stratification revealed significantly better PFS in patients with liver-limited metastases compared to those with concurrent hepatic and extrahepatic metastases (P = 0.0003). CONCLUSION: HAIC oxaliplatin plus 5-FU/FUDR is a robust regimen for treatment-resistant CRC patients with unresectable CRLM, particularly those with liver-limited disease.