Background: The prognosis of traditional treatments for patients with HCC was dismal. Small-molecule anti-angiogenic targeted drugs and PD-1 blockades have been shown superior efficacy in advanced HCC. As a novel oral multitarget TKI, anlotinib monotherapy or combined with PD-1 blockades has preliminary efficacy in the treatment of HCC. Consequently, this study was to explore the efficacy and safety of anlotinib as first-line treatment and followed by TKIs combined with PD-1 blockades regimen after disease progression for advanced HCC in real-world. Methods: Patients with advanced HCC with BCLC stage B or C were recruited in this study. Eligible patients received anlotinib (8/10/12mg, po, d1̃14, q3w. Dosage is determined by the clinician) as first-line treatment until disease progression or intolerable toxicity. For those with progressive disease, treatment was administrated with TKIs (anlotinib, apatinib, lenvatinib, or regorafenib) and PD-1 blockades (camrelizumab or sintilimab) until disease progression again or intolerable toxicity. The primary endpoint was PFS (RECIST v 1.1) in the first-line treatment. Secondary endpoints were ORR, DCR, OS and safety. Results: From Feb 2019 to Nov 2021, a total of 62 eligible patients were enrolled. The patients were 55 (38̃78) years of age, including ECOG PS 0 (82.3%) or 1 (17.7%), BCLC stage B (32.3%) or C (67.7%). In the first line treatment, there were 12 CR (19.4%), 17 PR (27.4%), 25 SD (40.3%) and 8 PD (12.9%). Consequently, ORR was 46.8% (95%CI: 34.0%̃59.9%) and DCR was 87.1% (95%CI: 76.1%̃94.3%). At the cut-off date, 41 patients experienced disease progression, the preliminary median PFS was 7.37 months (95%CI: 5.88-8.86), and the median OS was not yet reached. Of the 41 patients with disease progression, 11 patients received TKIs plus PD-1 blockades regimen. There were 3 CR (27.3%), 1 PR (9.1%), 3 SD (27.3%) and 4 PD (36.4%). Therefore, ORR was 36.4% (95%CI: 10.9%̃69.2%) and DCR was 63.6% (95%CI: 30.8%̃89.1%). The safety profile suggested that the most common treatment-emergent adverse events were thrombocytopenia (51.6%), leukopenia (50%), hypertension (46.8%), neutropenia (46.8%), fatigue (43.5%) and hand-foot syndrome (41.9%). The common grade ≥3 treatment-emergent adverse events were hypertension (12.9%), elevated bilirubin (9.7%) and neutropenia (7.9%). Unfortunately, one patient died from gastrointestinal bleeding. Conclusions: The present study indicated that anlotinib as first-line treatment and followed by TKIs combined with PD-1 blockades regimen after disease progression for advanced HCC exhibited potential efficacy and tolerable safety profile in real-world setting. The conclusion should be validated in more pts included subsequently.