Background: Hepatectomy is a key treatment for long-term survival in patients (pts) with HCC, but a high recurrence rate seriously affects the prognosis. Currently, there is no standard treatment for adjuvant therapy, transarterial chemoembolization (TACE), anti-angiogenic therapy, immune checkpoint inhibitor (ICI) therapy, or combination strategies being evaluated. Donafenib as first-line systemic therapy is recommended in advanced HCC, but this as adjuvant therapy is still explored. This study evaluated the efficacy and safety of donafenib-containing regimens as postoperative adjuvant therapies in HCC. Methods: We retrospectively reviewed the data of pts who had received donafenib monotherapy (D) or a combined regimen (D+TACE, D+ICI, or D+TACE+ICI) as adjuvant therapy in 5 Chinese centers from June 2021 to December 2022. Recurrence was assessed using imaging. A high-risk (HR) subpopulation was defined as pts with any of the following conditions: [i] single lesion >5 cm or multiple lesions of any size; [ii] lesion(s) complicated by tumor thrombus (TT); and [iii] microvascular invasion (MVI) grade ≥1. We analyzed the median relapse-free survival (mRFS) and one-year cumulative recurrence-free survival rate (1y-RFS) of the overall population and HR subpopulation, and safety (CTCAE5.0) of the overall population. Results: This study included 102 pts. At the data cut-off, mRFS had not yet been achieved, with a 1y-RFS rate of 78.2%; 12 pts (11.8%) experienced recurrence. In the HR subpopulation (N=80), the 1y-RFS rate was 79.4%, based on different treatment regimens, the 1y-RFS rates of the D (n=20), D+TACE (n=26), D+ICI (n=23), and D+TACE+ICI (n=11) groups were 87.5%, 87.7%, 72.4%, and 74.1%, respectively, and mRFS had not yet been reached; based on different clinical stages, the 1y-RFS rates of pts with China liver cancer staging stage Ib (n=35) and IIa (n=15) were 93.3% and 71.6%, respectively, with stage Ⅰa (n=12) and Ⅱb (n=7) were not reached, mRFS with IIIa (n=11) was 8.9 months (95% CI: 2.9–15.0 months). Among the overall population, 68 pts (66.7%) had treatment-related adverse events (TRAE) of any grade, and the incidence of grade 3 TRAE was 8.8% (9/102). None of the pts experienced grade 4 or 5 TRAE. Conclusions: These results preliminarily showed that donafenib-containing regimens as postoperative adjuvant therapies were safe and effective for HCC.