Background: The IMbrave 150 study opened the door of immuno-oncology (IO) combined with targeted therapy in patients (pts) with hepatocellular carcinoma (HCC). At present, some other combination of IO and tyrosine kinase inhibitors (TKIs) had been proved as efficient regimens in China and there are many ongoing studies on this approach with preliminarily considerable efficacy. Furthermore, the efficacy of this combination still needs to be explored in real-world patients. The aim of this study is to explore the efficacy and safety of anlotinib plus PD-1 inhibitors in the treatment of HCC in real-world. Methods: This is a multi-center, prospective real-world study in pts (N=200) diagnosed as advanced HCC, who evaluated by physician would get benefits from anlotinib alone or in combination with PD-1 inhibitors. The enrolled patients received treatment according to physicians. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigators according to RECIST version 1.1. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of data cutoff date of Aug, 2022, a total of 119 patients were enrolled with a median age of 55 years (range 29-83). Among them 78% ECOG PS 0-1, 21% ECOG PS 2 and 1% ECOG PS 4. 75 pts received anlotinib plus PD-1 inhibitors as first-line treatment, 17 pts as second-line treatment and 7 pts as third-line and above. 76 patients were eligible for response evaluation. The ORR as best response was 11.8% (95%CI: 5.6%, 21.3%). The DCR was 73.7% (95%CI: 62.3%, 83.1%). The preliminarily results indicated that the median OS was 12.5 months (95%CI: 9.7, 15.4), the median PFS was 8.1 months (95%CI: 5.9, 10.3). Any grade treatment-related adverse events (TRAEs) observed in 50% of pts. The most common TRAEs were hypoalbuminemia (18.6%), hypertension (11.4%), decreased white blood cell count (11.4%) and decreased platelet count (10%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 inhibitors exhibited potential efficacy and manageable adverse events in the treatment of advanced HCC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521.