Objective The objective of this study was to investigate the effect of depression on serum levels of C-reactive protein(CRP)and high-sensitivity C-reactive protein(hs-CRP),and prognosis in liver cancer patients. Methods A total of 251 patients with liver cancer undergoing hepatectomy were enrolled. The hospital anxiety and depression scale( HADS-D) and 9-item patients health questionnaire(PHQ9) were assessed for depression before 3 days for surgery. Patients were divided into depression group(n=95)and non-depression group(n=156) according to the scores. Preoperative serum levels of CRP,hs-CRP,ALT and AST were measured and compared between the depression and non-depression groups. Survival analysis Kaplan-Meier method was used to compare the disease-free survival(DFS)and total survival(OS)between the two groups. Results The serum levels of CRP, hs-CRP,ALT and AST in the depression group were significantly higher than those in the non-depression group(P<0. 05). The follow-up of 3. 5-year showed that 164 patients(65 in depression group and 99 in non-depression group)had recurrence or metas-tasis and 47 patients(22 in depression group and 25 in non-depression group) died. The DFS and OS in the depression group were significantly lower than those in the non-depression group(P< 0. 05). Cox multiple regression analysis showed that liver function grading,BCLC staging and depression were independent risk factors for the prognosis of liver cancer. Spearman correlation analysis showed that patients′degree of depression was positively correlated with serum levels of CRP and hs-CRP(P<0. 05),DFS and OS were negatively correlated with serum levels of CRP and hs-CRP(P<0. 05). Conclusion Depression may mediate elevated serum levels of CRP and hs-CRP,maintain inflammatory response in patients,lead to increased liver function damage,elevate levels of ALT and AST,and thus adversely affect the prognosis of patients with liver cancer.