Disease and mortality rates for Streptococcus pneumoniae infections are much higher in patients with sickle cell disease (SCD) than in age-matched patients without SCD. Pneumococcal surface protein A (PspA) has been proposed as a component in human vaccines against S. pneumoniae to provide greater breadth of coverage than can be obtained with the 7-valent conjugate vaccine. The cross-reactivity of PspA is associated with the 'PspA family' structure. In this study we examined strains of S. pneumoniae from patients with and without SCD to determine whether the strains infecting the hypersusceptible population of SCD patients were limited to the same two PspA families already known to comprise over 95% of strains infecting non-SCD patients. Each strain was also evaluated according to the presence or absence of specific PCR fragments based on repetitive BOX elements to screen for possible SCD-associated clonal structure. Strains from SCD and non-SCD patients were similarly dispersed among the most common BOX PCR groups and strains from both groups expressed a similar distribution of PspA variants. Thus, a PspA vaccine designed for the population at large should also be appropriate for patients with SCD. © 2004 Cambridge University Press.