In the past, patients with liver cancer who lost surgical treatment were mainly treated with sorafenib and other therapeutic means. Donafinib is an updated version of sorafenib and also the only monotherapy drug to date that has been superior to sorafenib in OS in a first-line head-to-head study in advanced HCC. This study aimed to evaluate safety and efficacy of transarterial chemoembolization (TACE) combined with donafenib in a real word cohort of patients with intermediate and advanced hepatocellular carcinoma. Prospective analysis of 27 patients with intermediate or advanced primary HCC treated at the from Shandong Cancer Hospital and Institute December 2021, including 19 cases treated with TACE combined with donafenib and 9 cases treated with TACE combined with donafenib and programmed death-1 (PD-1) inhibitor. TACE was administered as needed, and TKI medication were initiated within two and three days after TACE and/or plus PD-1, respectively. Radiological response was recorded by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and every 6-12 weeks after treatment initiation.Tumor response was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). As of the data cutoff on September 30st, 2022, the median duration of follow-up was 5.6 (0.9–18) months. The median PFS was 9.9 months (95% CI: 5.7-14.1)mTTR was 1.3 months (95% CI: 1.1-2.3)and the median OS was not reached. According to mRECIST,the ORR rate was 51.9% (14/27), and the DCR rate was 88.9% (24/27) .Four patients (14.8%) successfully underwent conversion therapy and all achieved R0 resection. One patients achieved a complete pathological response, Three achieved a major pathological response. All treatment related adverse events were tolerated. No serious adverse events were observed, and no treatment-related deaths occurred. TACE combined with donafenib treatment for intermediate to advanced unresectable HCC was effective, with good tumor responsiveness, high surgical conversion rate, and safe and controllable adverse reactions during treatment.