Drug-eluting microsphere transarterial chemoembolization (DEM-TACE) reduces systemic exposure to chemotherapeutic drugs compared with conventional TACE but permanently occludes the embolized vessels, potentially obviating the possibility of re-treatment with TACE. Temporary embolization by resorbable BioPearl™ microspheres might facilitate subsequent re-treatments. We herein describe the trial protocol of BIOPEARL-ONE, a prospective, single-arm, multicenter, post-market clinical follow-up study. The primary objectives are technical success and safety following the use. DEM-TACE with doxorubicin-loaded BioPearl™ for unresectable hepatocellular carcinoma (HCC). The secondary objectives are tumor response, duration of response, progression-free survival, and survival rate at 18 months. Fifty patients with HCC nodules smaller than 5 cm and within the up-to-7 criteria will be enrolled.