Thalassemia is a common hereditary hemoglobinopathy found largely in the “Thalassemia Belt”. Thalassemia children are at risk of the hepatitis B virus (HBV) infection, given the frequent need for blood transfusions. The immune dysregulation underlying these diseases may lead to defective long-term protection even after full HBV vaccination. This study will evaluate the efficacy of an additional hepatitis B vaccine and will screen the influencing factors that affect immune responses of thalassemia children. All subjects were screened from August 2023 to July 2024 at Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia, where 126 pediatric patients (3–18 years of age) were diagnosed with thalassemia. All the participants had previously received the Indonesian national hepatitis B vaccination program. Seventy two eligible children who exhibited negative immune protection against hepatitis B accordingly received a single booster dose of hepatitis B vaccine. One month later the immune response was assessed by determination of anti-HBs titers. Logistic regression was used to evaluate significant predictors of the anti-HBs titer. Age, gender, type of thalassemia, transfusion interval, ferritin levels, nutritional status, and splenectomy were compared with post vaccine anti-HBs levels. Following the booster, protective immunity was present in 75% of children and high protective titers were present in 50%. The predictors of post-booster anti-HBs level included age (OR = 0.5; CI = 0.2–0.8; p = 0.018) and splenectomy. Children with transfusion-dependent thalassemia, aged over 3 years, are recommended to receive a booster dose of the hepatitis B vaccine. © The Author(s) 2025.