Human FcgammaRIIa has 2 codominantly expressed allotypes, which differ greatly in their ability to ligate immunoglobulin G2 (IgG2). Whereas FcgammaRIIa-R131 binds only weakly to IgG2, FcgammaRIIa-H131 binds to it efficiently and might be primarily responsible for the phagocytosis of IgG2-opsonized bacteria. IgG2 plays a pivotal role in defense against pneumococcal infection. This prospective study showed that 50% of patients with bacteremic pneumococcal pneumonia were homozygous for FcgammaRIIa-R131, compared with 28% with nonbacteremic pneumococcal pneumonia and 29% of uninfected controls (P<.05). The gene frequency of FcgammaRIIa-R131 was 0.67 in bacteremic patients, significantly higher than in the other groups (P<.05). All bacteremic patients who died within 1 week of hospitalization were homozygous for FcgammaRIIa-R131. Therefore, the severity of pneumococcal infection may, in part, be genetically mediated. Taken together with similar findings in cases of meningococcal disease, these results suggest that such genetic factors may be generalizable to infections caused by encapsulated bacteria.