Invasive pneumococcal infection continues to be a significant cause of morbidity and mortality especially in patients with antibody deficiencies and disorders affecting the reticulo-endothelial system. Current recommendations for prophylaxis in these patients include immunization with 23-valent pneumococcal polysaccharide capsular vaccines. Post-immunization responses are commonly assessed by measuring serum antibody levels. However, there is no defined protective antibody range and this approach fails to determine the functional capacity of the antibodies. A simple, reproducible flow cytometric method of assessing the antibody-mediated opsonic activity against S. pneumoniae is described. This assay detected defective opsonic function in post-immunized at-risk patients who developed invasive pneumococcal infection.