Introduction: Response rates to systemic chemotherapy for patients who have failed irinotecan-based chemotherapy for liver-dominant metastatic colorectal cancer range between 10 and 18 % with overall survival between 7 and 9 months. The aim of this study was to assess the efficacy and safety of hepatic arterial irinotecan therapy in patients with hepatic-dominant metastatic colorectal cancer who had failed systemic irinotecan. Methods: This was a multi-institutional, multi-national, analysis of patients who received DEBIRI in the setting of unresectable liver-dominant metastatic colorectal cancer. Patients had received between 1 and 4 lines of prior chemotherapy, the majority of which included systemic irinotecan. Primary endpoints were toxicity profile and tumor response rate. Results: 296 patients with unresectable liver metastases who had undergone 666 DEBIRI treatments were reviewed. 192 treatments were performed in patients who had received prior systemic irinotecan. 222 treatments were performed in irinotecan-naïve patients. The median number of DEBIRI treatments was 1 (range 1-8); median treatment dose was 100 mg (range 50-200 mg), with total hepatic treatment of approximately 100 mg (range 20/30-200/300 mg). All-grade adverse events occurred in 18 % of patients receiving prior systemic irinotecan compared with 15 % of patients receiving no prior systemic irinotecan (including chemo-naïve patients). Response rates in patients with prior systemic irinotecan were 44 % at 3 months, 43 % at 6 months, and 44 % at 12 months, compared with 45, 40, and 35 % during the same time point in patients without prior systemic irinotecan. All-grade adverse events occurred in 10, 20, 10, and 37 % of patients receiving 0, 1, 2, and 3+ lines of systemic chemotherapy, respectively. Overall survival was 90 %, 93 %, 90 %, 90 % at 6 months and 76 %, 71 %, 77 %, 87 % at 12 months in patients undergoing DEBIRI therapy after receiving 0, 1, 2, and 3+ lines of systemic chemotherapy, respectively. Conclusions: The safety and efficacy of hepatic arterial drug-eluting irinotecan bead (DEBIRI) therapy are not affected by non-response to prior systemic irinotecan. While DEBIRI complete response rates are greatest and overall adverse events are least in chemotherapy-naïve individuals, it retains its respectable efficacy and low rate of serious adverse events even in the setting of previous administration of systemic chemotherapy.