Background: To explore the prognosis of patients with continuing regorafenib therapy after the HCC progression of second-line regorafenib therapy. Methods: The HCC patients with second treatment by regorafenib from Dec. 2017 to Dec. 2021 were collected from His system of the hospital. The inclusion criteria included surgical treatment with hepatectomy or liver transplantation, the HCC diagnosis by pathological confirmed, Child-Pugh A-B and ECOG PS≤2 when taking regorafenib, exposure time ≥21 days. Efficacy was evaluated according to RECIST v1.1 (solid tumor efficacy Evaluation Criteria). Results: By Dec. 31, 2022, the median follow-up time was 17.6 months since taking regorafenib. The median overall survival (OS) time was 26.0 months (95%CI 19.75-32.25 months) in 110 patients with second-line regorafenib treatment for recurrent HCC after surgical treatment, and the median OS time of first-line sequential regorafenib was 37.6 months (95%CI 30.23-44.97 months). In 100 cases of regorafenib progression, 10 cases received only palliative therapy after progression. The ninety cases continued the antitumor therapy, the median OS time after progression was 18.0 months (95%CI 12.93-23.07). There were 56 patients (62.2%) who continued to take regorafenib and 34 patients (37.8%) who took other targeted drugs. The median OS time after progression in the two groups was 18.0 and 19.8 months, respectively (P=0.614). In 56 patients who continued regorafenib, Kaplan-Meier analysis and Cox regression risk model analysis showed that NLR≥4.0, liver tumor load larger and without combination therapy were independent risk factors for survival after progression in patients with continued regorafenib. Conclusions: The overall survival time 18.0 months was found in patients with HCC progression after second-line regorafenib therapy, these patients with recurrent HCC underwent surgical treatment (resection or liver transplantation). There was no significant difference in OS time between those who continued regorafenib therapy and those who selected other targeted agents after HCC progression with the regorafenib. The NLR≥4.0, liver tumor load lager, and without combination therapy were independent risk factors for survival after progression in patients who continued regorafenib.