Objective To investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) in patients with unresectable colorectal cancer liver metastases after multi-line treatment with drug resistance.Methods A total of 24 patients with unresectable colorectal cancer liver metastases receiving HAIC treatment in our hospital between July 2020 and December 2021 were collected, including 14 patients who had previously received second-line treatment and 10 patients who had received third-line treatment or above. HAIC treatment was performed once every 3~4 weeks. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), survival time (OS), and adverse reactions (AE) were followed up. The clinical characteristics affecting prognosis were analyzed by univariate and multivariate analysis.Results A total of 56 HAIC treatments were performed in 24 patients, of which 2 cases were treated once, 14 were treated twice, 6 were treated three times, and 2 was treated four times. The ORR was 16.7% (4/24), and DCR was 62.5% (15/24). The incidence of grade 3~4 AE was 41.7% (10/24). The median progression-free survival (mPFS) was 3.4 months and the median survival (mOS) was 13.6 months. Univariate analysis showed that the number of tumors, the maximum diameter of tumors, extrahepatic metastasis and ECOG scores were associated with prognosis (P<0.05). Multivariate analysis showed that the number of tumors, the maximum diameter of tumors and ECOG scores were independent factors affecting prognosis (P<0.05).Conclusion HAIC is effective and has acceptable side effects after drug resistance to multi-line treatment for patients with unresectable colorectal cancer liver metastases. Patients with only intrahepatic metastasis, larger number of tumors, larger tumor diameter, and good performance status can benefit from HAIC. For patients with extrahepatic metastasis, systemic intravenous chemotherapy is also required.