Abstract. The value of serum cholinesterase (ChE) level as a predictive marker in sorafenib therapy for advanced hepatocellular carcinoma (HCC) has not yet been investigated. The present retrospective study therefore analyzed the impact of the serum ChE level in 93 patients with advanced HCC treated with sorafenib. Patients were categorized into two groups: group A with pretreatment serum ChE ≥140 IU/l (n=46) and group B with pretreatment serum ChE <140 IU/l (n=47). The correlation between clinicopathological findings, including serum ChE level, and overall survival (OS) and liver damage during sorafenib therapy was investigated. The median OS of the patients was 275 days, while OS was markedly higher in group A compared to group B (P=0.002). In 70 Child-Pugh A patients, serum ChE level was a significant prognostic predictor in multivariate analysis [P=0.019, hazard ratio (HR) =2.612; 95% confidence interval (CI), 1.174-5.810]. During sorafenib treatment, 22 patients developed liver dysfunction of grade 3 or higher. Only two group A patients (4.3%) developed liver dysfunction, compared to 20 group B patients (42.6%) (P<0.001). Multivariate analysis demonstrated that the pretreatment serum ChE level was the strongest predictor of liver damage (P= 0.002, HR= 0.061, 95% CI: 0.010-0.373), indicating serum ChE <140 IU/l to be the only independent predictor associated with severe liver function damage during sorafenib treatment in 70 patients with grade A Child-Pugh (P= 0.016; HR= 0.122; 95% CI, 0.022-0.676). In conclusion, lower serum ChE level is a significant predictor of poor prognosis and severe liver damage in HCC patients treated with sorafenib. Advanced HCC patients with lower serum ChE levels, including those with a Child-Pugh A pretreatment liver function score, should be given sorafenib therapy with caution.