Because the Neisseria meningitidis serogroup B (NMSB) capsule is poorly immunogenic in humans, immunization strategies have focused on noncapsular antigens. Both PorA and to a lesser extent PorB are noncapsular protein antigens capable of inducing protective bactericidal antibodies, and vaccines based on the outer membrane protein (OMP) components of serogroup B meningococci have been shown to be effective in clinical trials. Multiple PorA antigens seem to be needed to prevent endemic meningococcal disease around the world, and a hexavalent PorA-based meningococcal vaccine has recently been developed in The Netherlands. To evaluate the distribution of NMSB PorA and PorB antigens in the United States, serosubtyping and serotyping were done on 444 NMSB strains isolated in the active surveillance areas of the United States (total population, 32 million) during the period 1992 to 1998. A total of 244 strains were isolated from sporadic cases of meningococcal disease, and 200 strains were isolated from an epidemic in Oregon. A panel of 16 mouse monoclonal antibodies reactive with PorA and 15 monoclonal antibodies reactive with PorB were used. Among the NMSB isolates obtained from sporadic cases, the most prevalent serosubtypes were P1.7,16 (14.3%), P1.19,15 (9.8%), P1.7,1 (8.6%), P1.5,2 (7.8%), P1.22a, 14 (7.8%), and P1.14 (5.3%) and the most prevalent serotypes were 4,7 (27.5%), 15 (16%), 14 (8.6%), 10 (6.1%), 1 (4.9%), and 2a (3.7%). A multivalent PorA-based OMP vaccine aimed at the six most prevalent serosubtypes could have targeted about half of the sporadic cases of NMSB disease that occurred between 1992 and 1998 in the surveillance areas. Twenty serosubtypes would have had to be included in a multivalent vaccine to achieve 80% coverage of strains causing sporadic disease. The relatively large number of isolates that did not react with routine monoclonal antibodies indicates that DNA sequence-based variable region typing of NMSB will be necessary to provide precise information on the distribution and diversity of PorA antigens and correlation with nonserosubtypeable isolates. The high degree of variability observed in the PorA and PorB proteins of NMSB in the United States suggests that vaccine strategies not based on OMPs should be further investigated.