Purpose Anlotinib, a novel multi-target tyrosine kinase inhibitor, has shown encouraging antitumor effects in advanced hepatocellular carcinoma (HCC). This study evaluated the effectiveness and safety of anlotinib with or without programmed death-1 (PD-1) blockades for patients with advanced primary HCC in a real-world setting in China. Patients and Methods Between July 2019 and May 2021, 27 patients with advanced primary HCC who received at least 2 cycles of anlotinib were included in this retrospective study. Primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Of the 27 patients, ORR and DCR were 25.93% and 74.07%, respectively. The median follow-up time was 6.27 months (range: 1.30–17.40) with a median PFS and OS of 3.29 months (95% CI: 1.31–15.47) and 6.21 months (95% CI: 2.23–15.87), respectively. A total of 14 patients received anlotinib and PD-1 blockade combination therapy, and 13 received anlotinib monotherapy. No significant differences were observed in ORR (28.57 vs 23.08%), DCR (71.43 vs 76.92%), PFS (3.38 [95% CI: 2.66–13.14] vs 11.86 months [95% CI: 4.27–15.93]) and OS (4.90 [95% CI: 2.56–13.60] vs 11.04 months [95% CI: 1.31–17.18]) between the two groups (all p >0.05). Treatment-related AEs were reported in 88.89% of patients. Grade 3 AE was bleeding, which occurred in 3 patients (11.11%). Conclusion Anlotinib yielded a promising efficacy and manageable safety in patients with advanced primary HCC irrespective of whether patients received PD-1 blockades, indicating that anlotinib might be a promising treatment option for this patient population.