Abstract Background: Hepatitis B virus (HBV) infection is the most common serious liver infection. The study aimed to evaluate the effect of a HBV protection intervention on interns, as regards their knowledge, attitude and immune response to HB vaccine and to identify the factors affecting their compliance and immune response to HB vaccination at Zagazig University Hospitals. Methods: A quasi-experimental study was conducted in 3 phases over 10 months. Phase 1: assessment of knowledge, attitude and HCV/HBV immune status. Phase 2: the implementation of HBV protection campaign; vaccine administration and health education sessions. Phase 3: the assessment of the immune response to the vaccine and the change in knowledge and attitude. Results: Out of 120 participants, 60% were compliant to the vaccination schedule. Needle-stick injury, the seriousness of HBV infection and attendance of infection control courses are the motivating factors to vaccination (p < 0.05). After the 3rd dose, 9.7% were non-responders. BMI and diabetes were the statistically significant predictors of the immune response. The HCWs compliant with vaccination schedule had higher mean scores regarding; total knowledge (15.5
2.1), p < 0.0001 and attitude (14.34
3.8) p < 0.05. A significant improvement is recorded from the posttest results, p < 0.000. Conclusions: A comprehensive protective program against HBV is an effective tool. A compulsory vaccination program is still needed for interns. Post vaccination monitoring program, including protective measures for vaccine non responders is urgently needed with strict follow