Background: Cirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC) with a yearly incidence ranging from 1 to 8%. EASL and AASLD guidelines recommend systematic screening with liver ultrasound at 6 months interval in cirrhotic patients. A glycomic based test, called GlycoCirrhoTest, based on to the respective abundance of bisecting GlcNAc residues and triantenarry glycans on serum proteins, has shown a 79% sensitivity and 86% specificity for the diagnosis of cirrhosis among patients with chronic liver diseases. The aim of the present study was to determine whether serum glycomics are predictive for the development of HCC in compensated cirrhotics. Methods: Blood samples of 132 cirrhotic (Child A or B) patients collected between 1995 and 2005 were analysed. Seventy percent suffered of Hepatitis C. In the remaining patients, the cause of cirrhosis was HBV infection, alcohol and autoimmune diseases. Cirrhosis was confirmed by liver biopsy. The patients were followed until the appearance of a HCC, death or liver transplantation. At the moment of serum sampling there was no evidence of HCC. GlycoCirrhoTest was performed using capillary electrophoreses as previously described by Callewaert et al. (Nature Medicine 2004). Results: After a median follow up of 4 years (IQR: 3.6–8.06), 35 (26.5%) of the patients developed a HCC. Mean follow up in the patients who did not develop HCC was 3.7 years (IQR: 3.4-9.9; ns) . There was a significant increase of the mean baseline GlycoCirrhoTest value in the patients who developed a HCC during follow up (p < 0.001) as compared to those who did not. ROC Curve analysis showed an AUC of 0.716 (95% CI: 0.611-0.820) for the prediction of HCC in the patients with a follow up of at least 1 year. An 0.1 increase in the value of the GlycoCirrhoTest was associated with a 27% increase in the risk for developing HCC (OR 1,27; 95%CI: 1,098-1,475). Conclusions: This study suggests that an analysis of the serum protein glycome could generate a useful biomarker for the identification of cirrhotic patients at high risk for the development of HCC. GlycoCirrhoTest may help to stratify cirrhotic patients according to the risk of HCC and optimize screening.