Background <p>Hepatic arterial infusion chemotherapy (HAIC) is a potentially attractive locoregional therapy for patients with unresectable colorectal liver metastases (CRLM). This study aimed to evaluate the safety and efficacy of FOLFOX-HAIC plus regorafenib in the treatment of unresectable CRLM refractory to first and second-line systemic chemotherapy.</p> Methods <p>A total of 35 patients with unresectable CRLM who underwent FOLFOX-HAIC plus regorafenib between July 2020 and January 2023 were included in this retrospective study. The objective response rate (ORR), disease-controlled rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse event were assessed. Factors affecting OS were analyzed.</p> Results <p>Kaplan–Meier curves showed that the median OS₁ (measured from the time of diagnosis), OS₂ (measured from the time of the first HAIC treatment) and PFS (measured from the time of the first HAIC treatment) were 29.0 (95%CI, 18.9–39.1) months, 21.0 (95%CI, 14.9–27.1) months and 13.0 (95%CI, 9.3–16.7) months, respectively. The ORRs at 3 months, 6 months and 12 months after HAIC were 57.1%, 45.7% and 22.9%, respectively, and the DCRs were 88.6%, 80.0% and 51.4%, respectively. No grade 5 adverse events (AEs) (death) were observed. Common Regorafenib-related AEs were hand-foot skin reaction (<i>n</i> = 18, 51.4%) and fatigue (<i>n</i> = 15, 42.9%). Common HAIC-related AEs were weight loss (<i>n</i> = 28, 80.0%), abdominal pain (<i>n</i> = 19, 54.3%) and nausea (<i>n</i> = 15, 42.9%).</p> Conclusions <p>FOLFOX-HAIC plus regorafenib might be beneficial and tolerable in the treatment of unresectable CRLM refractory to first and second-line systemic chemotherapy.</p>