Background: TACE is well-recognized as the mainstay treatment for intermediate-stage HCC; however, the efficacy of TACE monotherapy has been unsatisfactory in advanced-stage HCC. Donafenib is a novel multi-kinase inhibitor approved for first-line treatment of advanced-stage HCC. Herein, we evaluated the efficacy and safety of donafenib combined with TACE for treating intermediate/advanced-stage HCC. Methods: We collected clinical data of patients (pts) with unresectable HCC who had a Child-Pugh class A/B and were admitted for donafenib and TACE combination therapy at The First Affiliated Hospital of USTC between October 2021 to October 2022. Pts had at least one measurable lesion determined using mRECIST criteria. Pts with complete baseline information and at least one follow-up evaluation were incorporated in the final analysis, including the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) by CTCAE 5.0. The last follow-up time was January 1, 2023. Results: In total, 109 pts were enrolled (80.3% males, mean age 60.5 years, 86.2% ECOG of 1, 92.7% HBV positive, 53.2% BCLC stage B, 46.8% BCLC stage C, 31.2% baseline AFP≥400 μg/L, 39.5% with portal vein tumor thrombus). Among them, 54 pts (49.5%) received donafenib combined with TACE as first-line treatment, 8 (7.3%) as second-line treatment, and 47 (43.2%) with concurrent immunotherapy. At the time of data cut-off, the median follow-up time was 6.2 months, and 67 pts (61.5%) had ongoing donafenib treatment. The mean duration of treatment (DOT) with donafenib was 6.0 months, and the longest DOT was 12 months. Considering efficacy, 30 pts (27.5%) achieved complete response, 54 (49.5%) achieved partial response, 17 (15.6%) had stable disease, and 8 (7.4%) had progressive disease. The ORR and DCR were 77.1% and 92.7%, respectively. The ORRs of the first-, second-, and combination immunotherapy groups were 77.8% (42/54), 50.0% (4/8), and 80.9% (38/47), respectively. The DCRs were 92.6% (50/54), 100% (8/8), and 91.5% (43/47), respectively. Median progression-free survival was not reached. In terms of safety, 89 pts (81.7%) had AEs. The incidence of ≥grade 3 AEs was 17.4% (19/109), and the incidence of drug withdrawal due to AEs was 4.6% (5/109). The most common AEs were diarrhea (31.2%), hand-foot syndrome (29.4%), fatigue (25.7%), rash (15.6%), nausea (10.1%), and xerostomia (4.6%). The incidences of ≥grade 3 AEs in the first-, second-, and combination immunotherapy groups were 14.8% (8/54), 12.5% (1/8), and 17.0% (8/47), respectively. The combination immunotherapy group exhibited a high incidence of AEs. Conclusions: Satisfactory disease control was achieved in pts with different treatment durations after receiving donafenib combined with TACE, along with favorable safety and tolerability.