Objective: To evaluate the efficacy of anlotinib in the treatment of advanced hepatocellular carcinoma (HCC) and to explore the prognostic factors. Methods: A total of 70 patients with advanced HCC receiving anlotinib were retrospectively analyzed. The short-term objective efficacy and adverse reactions were observed, and the effects of clinical factors on the short-term efficacy were analyzed. Kaplan-Meier was used for survival analysis. Cox regression model was used for univariate analysis and multivariate analysis to evaluate the relationship between clinical factors and survival. Results: Among the 70 patients treated with anlotinib, there were 0 cases of complete remission, 22 cases of partial remission, 28 cases of stable disease, and 20 cases of disease progression. The objective remission rate was 31.43%, and the disease control rate was 71.43%. The disease control rate of patients with Eastern Cooperative Oncology Group (ECOG) score of 0–1 was significantly higher than that of patients with ECOG score of 2 (P<0.05), whereas other clinical factors such as age and gender had no significant effect on disease control rate (P>0.05). Patients were followed up for 2–15 months, and the median OS was 7.4 months (95%CI: 6.9 to 8.7). Cox regression analysis showed that the ECOG score (HR=1.402, P<0.001)and ALB level (HR=1.572, P=0.011) were independent predictors. Patients with ECOG score of 0–1 had longer median OS than patients with ECOG score of 2 (P=0.034). Patients with albumin (ALB) >35 g/L had longer median OS than patients with ALB ≤35 g/L (P=0.019). The common adverse reactions of anlotinib were hand-foot syndrome (38.57%), hypertension (25.71%), proteinuria (21.43%), and thrombocytopenia (18.57%), which were grade 1–2, and no adverse reactions above grade 3. Conclusion: Anlotinib is effective and safe in the treatment of advanced HCC. ECOG score and ALB level are independent prognostic factors.