Patients with hematological diseases undergoing diagnostic or therapeutic splenectomy are at increased risk of acquiring fulminant pneumococcal infections. Vaccination is a straightforward option in reducing these infections. Certain patient subgroups showing inadequate immunological response to pneumococcal vaccination may be candidates for alternative prophylactic measures. We prospectively studied the antibody response to vaccination with 23-valent pneumococcal capsular polysaccharide vaccine (Pneumovax N) in splenectomized patients with hematological disorders in relation to clinical characteristics and pneumococcal disease. A total of 76 splenectomized patients (Hodgkin s lymphoma 26, indolent lymphoma 10, aggressive lymphoma 8, immune hemolytic anemia 6, immune thrombocytopenic purpura 22, and others 4) with a median age of 52 years (range 18–82) were included. Antibody titers were determined using an enzyme-linked immunosorbent assay before and 12 months after vaccination. A weak immunological response was observed in 27 (35%) patients (poor responders) and an adequate response in 49 (65%) (good responders). During the follow-up period of 5–9 years after vaccination and despite repeated revaccination in many cases, a total of 5 episodes of microbiologically verified pneumococcal infections were reported in poor responders, while only one episode was noted among good responders (p=.01). Underlying malignant hematological diseases were more frequent among poor responders than among good responders (p=.002). The distribution of patients according to age, gender, immunoglobulin levels, time between splenectomy and vaccination (<1 year>), time between preceding chemotherapy/radiotherapy and vaccination (<6 months>) and/or previous radiotherapy did not differ between poor and good responders. In conclusion, a significant number of splenectomized patients with hematological diseases respond poorly to pneumococcal vaccination and have a significantly increased risk of post-splenectomy pneumococcal infections despite vaccination. In the absence of clinical parameters that can reliably predict a poor antibody response, measurement of antibody titers 12 months after vaccination seems to be the most adequate method for identification of patients in this subgroup. Poor responders may be offered other prophylactic measures such as antibiotic prophylaxis and/or immunization with pneumococcal conjugate vaccines. Studies to further elucidate the last alternative are ongoing.