AIM: The utility of serum alpha-fetoprotein (α-FP) in the detection of hepatocellular carcinoma (HCC) is questionable. Very high circulating levels of nociceptin/orphanin FQ (N/OFQ), a ligand for a novel opioid receptor, have recently been reported in HCC. The aim of this study was to assess the role of plasma N/OFQ in the diagnosis of HCC arising in patients with liver cirrhosis.METHODS: Plasma N/OFQ levels were measured by ELISA in 58 patients (28 HCC and 30 liver cirrhosis) and in 25 healthy controls. The values were correlated with clinical and laboratory features including α-FP. Spearman index, biserial correlation coefficient, non parametric combination (NPC) test and discriminant stepwise analysis were used for statistical evaluation of data.RESULTS: The upper normal limit of nociceptin was 122 pg/mL. Plasma levels above this cut-off were found in 21.4% of patients with HCC, in 23.3% of those with cirrhosis and in 8% of healthy subjects. α-FP serum levels ＞ 200 ng/mL were found in 46.4% of the patients with HCC and in none of those with cirrhosis. No correlation was found between N/OFQ levels and any of the clinical and laboratory features, including α-FP.By NPC test, HCC and cirrhotic patients were different with regard to α-FP (P = 0.000) but not in terms of nociceptin (P = 0.595). By point biserial correlation, HCC presence was positively correlated with α-FP (rpb = 0.52, P = 0.000) but not with N/OFQ (rpb = 0.16, P = 0.157). In a discriminant analysis, α-FP was significant in the Wilks test (Y = -0.709 + 0.03 α-FP) and properly classified 81% of all patients and 61% of HCC. N/OFQ had lower sensitivity, specificity and predictive values than α-FP.CONCLUSION: Nociceptin is increased in patients with chronic liver disease, independently of the presence of HCC, although the underlying mechanism has yet to be clarified. We conclude it is not a useful marker for HCC.