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Chronic liver disease results in a low response rate to the hepatitis B virus vaccine. Information on the efficacy of the double adjuvanted vaccine FENDRIX® (3-O-desacyl-4’-monophosphoryl lipid A and aluminum phosphate) and single adjuvant HBVAXPRO®40 (aluminum hydroxyphosphate sulfate) in chronic liver disease is scarce. The primary aim of this prospective study in clinical practice was to evaluate the effectiveness of HBVAXPRO®40 and FENDRIX® in this setting. Patients received HBVAXPRO® (0, 1 and 6 months) or FENDRIX® (0, 1, 2 and 6 months) depending on availability. Clinical data and anti-HBs levels were collected at 2, 6 and 12 months. A total of 125 patients were included (mean age 61.8 years; 57.6% males; 43.2% liver cirrhosis; 75.9% Child A and 24.1% Child B): 76 were vaccinated with HBVAXPRO® and 49 with FENDRIX®. There were no significant differences between the two vaccines. The overall response rates at 2, 6 and 12 months were 76.8, 72.8 and 59.2%, respectively. In the univariate analysis, active alcohol intake, alcohol etiology, liver cirrhosis and ultrasound signs of portal hypertension were associated with a lower response to vaccination, whereas in the multivariate analysis, liver cirrhosis was the only factor that significantly increased the likelihood of nonresponse (OR 10.5). HBVAXPRO® and FENDRIX® are good options for HBV vaccination in patients with chronic liver disease.