The spleen plays a paramount role in the host protection against invading microorganisms. In support of the above concept, in splenectomized patients there is increasing evidence of overwhelming postsplenectomy infections (OPSI). OPSI are caused by Streptococcus pneumoniae in about 80% of cases, but also Gram-negative bacteria are implicated in a certain number of cases. Therapeutically, penicillin and pneumococcal vaccines represent valid therapeutic approaches in Gram-positive OPSI. However, the effectiveness of polyvalent polysaccharide pneumococcal vaccines is still debated and, thus, other therapeutic strategies should be validated for combating OPSI. According to our personal data, a deficit of phagocytic activities and of T helper (h)-1 cells is very frequent in splenectomized patients. In sera, we found reduced levels of both Interferon-gamma and Interleukin (IL)-4. These data are in accordance with the recent observation on the protective role of T cells against S. pneumoniae. In fact, patients deficient in IL-12 develop severe pneumococcal infections and undergo apoptosis of Th(1) cells.