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Abstract: Background: Hepatocellular carcinoma (HCC) is the relevant cause of death in patients with compensated cirrhosis. Alpha-fetoprotein (AFP) is used for screening HCC, with limited success. Aim: We evaluated plasma chromogranin A (CgA) as a marker of HCC. Patients: CgA plasma levels and AFP serum levels were prospectively measured in 30 patients with HCC, 14 with cirrhosis, 79 with chronic hepatitis and 65 controls. Methods: CgA was measured with an enzyme-linked immunosorbent assay (DAKO A/S Glostrup, Denmark). AFP was measured by electrochemiluminoimmunoassay (Elecsys, Roche S.p.A., Italy). Results: CgA levels were significantly higher in the three groups of patients than in controls and in patients with HCC they were significantly higher than in chronic hepatitis patients [median 44.5 (interquartile range 21–145.9)U/L vs. 15.3 (10.9–29.25)U/L, p <0.001]. AFP values were above the upper reference limit in 75% of patients with HCC, 50% of cirrhotic patients and 11% of chronic hepatitis patients (p <0.005). CgA values significantly correlated with AFP levels (r s =0.42, p <0.0001). The overall diagnostic accuracy of CgA was 75% (CI 66–82), with a sensitivity of 70% (CI 50.6–85.2) and a specificity of 67% (CI 55.9–76.3). Conclusions: Despite the evidence of higher CgA levels in patients with HCC, this test has low-diagnostic accuracy. Its pathophysiological meaning remains unknown, even if it could suggest an endocrine phenotype of HCC. [Copyright &y& Elsevier]