Background: Donafenib, a deuterated derivative of sorafenib, significantly prolonged overall survival (OS) in patients with advanced hepatocellular carcinoma in an open, randomized, parallel-controlled phase II/III trial (ZGDH3) compared with sorafenib. The purpose of this study was to explore and analyse the OS benefits of donafenib and sorafenib treatment in patients with different short-term response and progression patterns. Methods: This analysis was based on the ITT population of ZGDH3 study (defined as all randomized patients). The median OS of donafenib and sorafenib was assessed by the Kaplan-Meier method and was compared according to different short-term response (SD, others) and progression patterns (intrahepatic lesion growth, intrahepatic new lesion, extrahepatic lesion growth, extrahepatic new lesion). The stratified Cox proportional hazard model was used to calculate the hazard ratio and its 95% confidence interval. Results: 668 patients were included in the analysis (334 in each group). Donafenib was associated with a trend of improved OS benefit when compared with sorafenib in most subgroups (HR < 1), including best short-term response of SD or others, confirmed short-term response of SD or others, intrahepatic lesion growth or not, intrahepatic new lesion or not, extrahepatic new lesion or not, no extrahepatic lesion growth. The benefit was statistically significant in the following subgroups: in patients with response of SD, the mOS of donafenib and sorafenib were 19.3 and 15.5 months, respectively (HR 0.714, 95%CI 0.550-0.928). Among patients with confirmed response of SD, the mOS was 29.0 and 22.8 months, respectively (HR 0.641, 95% CI 0.418-0.983). Among patients without extrahepatic lesion growth (defined as lesion growth ≥20% from baseline), the mOS was 12.6 months and 10.0 months, respectively (HR 0.783, 95% CI 0.648-0.945). Among patients without new extrahepatic lesions, the mOS was 13.1 months and 11.0 months (HR 0.816, 95% CI 0.677-0.998), respectively. Conclusions: Donafenib exhibited better survival benefit than sorafenib in most subgroups, especially in patients with the best response and confirmed best response of SD, which further confirmed the excellent efficacy of donafenib in first-line treatment of advanced HCC. Clinical trial information: NCT02645981.