- Background & aims: Response rate to second-generation Hepatitis B virus vaccines is relatively low in patients with inflammatory bowel diseases compared to the general healthy population.We compared the efficacy and safety of a third-versus second-generation Hepatitis B virus vaccine in a group of patients with inflammatory bowel diseases treated with immunosuppressive medications. Methods: Prospective, randomized, single-blinded, controlled study. Eligible patients were randomly assigned to receive one of two vaccines, ENGERIX-B or Sci-B-Vac. The vaccines were administered in three doses at 0, 1 and 6 months. Primary endpoint was defined as the titer of anti-HBs antibodies following standard three-dose Hepatitis B virus vaccination schedule. Results: Seventy-two patients complied with study protocol (37 and 35 patients in the ENGERIX-B and Sci-B-Vac groups respectively). Overall 75% of the cohort seroconverted. The Primary endpoint was met in 81.1% in the ENGERIX-B group and 68.6% in the Sci-B-Vac group (p=0.22). Patients in the Sci-B-Vac group showed statistically significant decreased seroconversion rate compared to the ENGERIX-B group, with use of TNF alpha inhibitors (p=0.03), and higher degree of disease activity (p=0.03). Conclusions: Overall seroconversion rate in our cohort was higher than in previous reports in the literature, possibly due to a low disease activity state in the majority of participants. Third generation Hepatitis B virus vaccines showed no apparent advantage over standard of care vaccine in this patient group. ClinicalTrials.gov number NCT01531075.