Hepatocyte growth factor (HGF), interleukin-6 (IL-6), and C-reactive protein (CRP) are acute-phase reactants that are usually present at high concentrations in the serum of patients with liver disease. However, the origin of these high serum concentrations is not completely understood, and whether hepatocellular carcinoma (HCC) tissue is a contributing factor is a controversial issue. The purpose of this study was to investigate the profiles of these three proteins in patients with HCC before and after tumor resection, and to study factors that might affect the serum concentrations of these proteins. A retrospective cohort study was performed in 34 consecutive patients who underwent HCC resection at the National Taiwan University Hospital. Blood samples were collected before surgery and on days 1, 3, 5, 7, and 14 postoperatively for serum concentration determinations of these three proteins. Twenty-three patients admitted for health examinations were enrolled as normal controls. Multiple regression analysis was conducted to evaluate the correlations between the pre- and postoperative cytokine concentrations and various clinical parameters. Compared with normal controls, the HCC patients had a significantly higher preoperative concentration of HGF (1,472 +/- 73 vs 948 +/- 54 ng/mL, p < 0.001) and IL-6 (44.1 +/- 6.9 vs 8.1 +/- 3.2 pg/mL, p = 0.012). These concentrations peaked on the first postoperative day and then declined to preoperative values on the fifth postoperative day. The CRP concentration was also higher in HCC patients (0.88 +/- 0.22 vs 0.21 +/- 0.06 mg/dL, p = 0.222), but the difference was not statistically significant. However, the CRP concentration did not return to the preoperative value within 2 weeks postoperatively. Preoperatively, HGF and CRP concentrations were positively affected by larger tumor size, and IL-6 concentration was negatively affected by hepatitis B surface antigen positivity and a higher indocyanine green (ICG) retention rate. In summary, the serum concentrations of HGF and IL-6 were significantly higher in HCC patients than in normal controls. The serum concentrations of HGF, IL-6, and CRP rose dramatically after HCC resection. The concentrations of these proteins were affected by different clinical parameters. We proved indirectly that high serum concentrations of HGF, IL-6, and CRP in patients with HCC do not result primarily from synthesis by the tumor cells. Whether the preoperative concentrations of these proteins correlate with the clinical outcome needs further follow-up.