Hepatitis B virus (HBV) is a vaccine preventable disease. Sufficient post vaccination response is critical step to achieve infection eradication. Vaccine hypo-responsiveness is a major risk factor for HBV chronic infection. We aimed to evaluate the effectiveness of birth dose HBV vaccine in preventing perinatal HBV infection and to detect the rate of HBV surface antibody (HBs-Ab) seroconversion and its relation to interleukin-4 polymorphism (IL-4 PM) among a group of vaccinated Egyptian infants. This observational analytical study involved 77 infants aged 6 to 12 months who received 4 doses of HBV vaccine including a zero dose. We measured serum levels of HBV-DNA and hepatitis B surface antigen (HBsAg) as markers of infectivity, and the level of (HBsAb) to assess vaccine responsiveness. Cytokine gene analysis to detect IL-4 gene polymorphism and its association with vaccine un-responsiveness were investigated. We observed that none of the vaccinated infants acquired HBV infection. Of the included 77 infants, seroconversion against HBV was detected in 72 (93.5%), 28 (36.4%) had low response and 44 (57.1%) had high response. While 5 (6.5%) were non responders. There was significant association between IL-4 gene polymorphism and the poor seroconversion after HBV vaccination. (p=0.03). Furthermore, HBsAb titer was significantly lower in children who have IL-4 gene polymorphism (p=0.014). In conclusion, implementation of birth-dose HBV vaccination is effective for prevention of perinatal infection, but seroconversion rate may be insufficient to induce long term protection. IL-4 gene polymorphism is associated with poor response to HBV vaccine.