Background: Results from the RESORCE-III RCT demonstrated that sequential sorafenib-regorafenib treatment significantly improved overall survival compared with the placebo group. However, there are no retrospective studies of regorafenib as a first-line agent for treating patients with advanced hepatocellular carcinoma in a real-world setting. Therefore, we aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with immune checkpoint inhibitors (ICIs) in treating patients with advanced hepatocellular carcinoma in a real-world setting. Methods: We reviewed medical data from 48 patients with advanced hepatocellular carcinoma treated with regorafenib as a first-line agent alone or combined with ICIs between December 2018 and February 2022. These patients were treated with regorafenib for at least 28 consecutive days (21 days on and 7 days off the drug). The progression-free survival (PFS), overall survival (OS), objective response rate (ORR, RECIST 1.1 criteria) and disease control rate (DCR) were observed. Results: A total of 48 patients were enrolled in this study, 26(54.2%) receiving regorafenib as monotherapy and 22(45.8%) receiving the combination ICIs. The median age in the monotherapy group was 54 years (range 38-74), male/female (69.2%/30.8%), BCLC stage B/C (42.3%/57.7%), Child-Pugh A/B score (57.7%/42.3%); the median age in the combined ICIs group was 53 years (range 42-75), male/female (68.2%/ 31.8%), BCLC stage B/C (36.4%/63.6%), Child-Pugh A/B score (54.5%/45.5%). Median PFS (mPFS) was 7.7 months (95% CI:5.9-10.4) and median OS (mOS) was 16.7 months (95% CI:14.3-23.6) in 48 patients. In the regorafenib monotherapy group, mPFS was 5.9 months (95% CI:5.6-10.3) and mOS was 13.9 months (95% CI:13.5-22.5); in the combined ICIs group, mPFS was 7.8 months (95% CI:7.3-14.5) and mOS was 23.6 months (95% CI:16.6-NA). The ORR and DCR were 20.8% and 72.9% in the overall treatment group, 15.4% and 65.4% in the monotherapy group, and 27.3% and 81.8% in the combined ICIs treatment group, respectively. Among the adverse events, rates were 34.6% (9/26) and 36.4% (8/22) in the monotherapy and combined ICIs groups, respectively, with only one grade III/IV adverse event in the monotherapy group and no grade III/IV adverse event in the combined ICIs group. Conclusions: This retrospective, real-world, preliminary study demonstrates that regorafenib as a first-line agent alone or in combination with ICIs has a high safety profile and more prolonged survival in patients with advanced hepatocellular carcinoma, particularly in combination with ICIs.