Immunization with pneumococcal surface protein A (PspA) from Streptococcus pneumoniae strain Rx1 cross-protects mice against challenge with diverse pneumococci. Truncated Rx1 PspA, consisting of amino acids 192-588, elicits protection against the mouse-virulent strain WU2. The possibility that homologous regions of other PspAs could also elicit cross-protection was investigated. Oligonucleotide primers designed according to the Rx1 pspA gene sequence were used to amplify chromosomal DNA from 15 diverse pneumococci. Three recombinant PspAs were evaluated for their ability to elicit protection in mice against challenge with 7 strains representing capsular types 3, 4, 5, 6A, and 6B. Two of the three truncated PspAs each elicited cross-protection against 71%-100% of the S. pneumoniae challenge strains examined. These data suggest that this technique may be useful for the generation of diverse PspAs for inclusion in a broadly protective pneumococcal vaccine.