Background: To analyze the perioperative safety and effectiveness of chemoembolization with CalliSpheres drug-eluting beads (DEBs) loaded with irinotecan (DEBIRI) in the treatment of unresectable colorectal cancer liver metastases (CRCLM). Methods: The clinical data of 16 colorectal cancer patients with postoperative liver metastases who were treated with chemoembolization using DEBIRI in our center from March 2017 to December 2018 were retrospectively analyzed. The treatment responses 3 and 6 months after the chemoembolization was evaluated with the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The clinical complications were recorded and graded. Changes in blood cells, liver function, and tumor marker were analyzed before treatment and during follow-up. Results: A total of 46 DEBIRI sessions were performed in 16 patients. The success rate was 100.0%. The main postoperative complications included right upper quadrant pain (76.1%), hypertension (87.0%), nausea (89.1%), and vomiting (84.8%), which were grade 1 to 2 events; one patient suffered from acute cholecystitis (2.2%), a grade 3 event. According to mRECIST, the complete response rate, partial response rate, objective response rate, and disease control rate were 0.0%, 68.7%, 68.7%, and 100.0% 3 months after chemoembolization and 0.0%, 81.2%, 81.2%, and 93.7% 6 months after the intervention. As shown by blood biochemistry, the carcinoembryonic antigen (CEA) significantly differed before treatment and during follow-up (P0.05). Conclusions: In this preliminary clinical study, chemoembolization with DEBIRI is safe and effective in treating unresectable CRCLM. However, more prospective multicenter clinical trials with larger sample sizes are required to confirm our findings further.