〔Abstract〕 Objective To assess the therapeutic efficacy of CalliSpheres drug-eluting microspheres in the interventional treatment of primary hepatocellular carcinoma. Methods From April 2020 to October 2022, twenty-five patients diagnosed with primary liver cancer admitted to Shenzhen Second People's Hospital underwent their initial Drug-Eluting Beads Transarterial Chemoembolization (DEB-TACE) procedure, utilizing CalliSpheres drug-eluting microspheres. Laboratory test variations, tumor activity lesion sizes before and after treatment, post-embolization adverse reactions, and medium to long-term prognosis were analyzed. Results The objective response rate (ORR) at 1, 3, and 6 months post-treatment were 55.56%, 61.54%, and 44.44%, respectively. The disease control rate (DCR) at 1, 3, and 6 months post-treatment were 88.89%, 76.92%, and 55.56%, respectively. The median overall survival (mOS) was 30.47 months [95% CI (16.02,44.91)] and the median progression-free survival (mPFS) was 19.21 months [95% CI (7.67,34.24)]. Compared to pre-treatment, there was no statistically significant difference in serum α-fetoprotein (AFP) levesl at 1 and 6 months post-treatment (P > 0.05), while AFP level at 3 months post-treatment decreased significantly (P < 0.05). After treatment, 22 patients (88%) experienced post-embolization syndrome, including abdominal pain in 18 cases (72%), nausea in 5 cases (20%), vomiting in 4 cases (16%), diarrhea in 2 cases (8%), fever in 6 cases (24%), fatigue in 5 cases (20%), headache in 1 case (4%), and bone marrow suppression in 8 cases (32%). No patients experienced severe complications such as gastrointestinal hemorrhage or liver abscess, and there were no treatment-related deaths. Conclusion CalliSpheres drug-eluting microspheres demonstrate favorable medium to long-term efficacy in the interventional treatment of hepatocellular carcinoma, and is an important treatment for patients with unresectable liver cancer patients.