Patients with thalassemia are at increased risk for infections, especially after undergoing splenectomy. Vaccinations and antimicrobial prophylaxis are recommended in these patients, but the optimal immunization schedule for Haemophilus influenzae type b (Hib) vaccine is unknown. The immunogenicity of a conjugate Hib vaccine was investigated in 57 patients with thalassemia, 32 of whom had undergone splenectomy. Anti-capsular antibodies to Hib (anti-polyribosylribitol phosphate) were measured before vaccination and 2, 6, 12, 24, and 36 months after vaccination. Immunization was well tolerated. All patients achieved protective (>1 microg/mL) antibody levels. Antibody titers declined after the initial postvaccination increase, becoming undetectable in 4 patients and decreasing to concentrations of 0.15-1 microg/mL in another 2 patients when tested 2-3 years after vaccination. Hib conjugate vaccine is safe and immunogenic in patients with thalassemia major; however, additional studies are needed to assess the need and timing of booster vaccination to maintain long-term immunity.