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After the widespread use of the 7-valent pneumococcal conjugate vaccine, replacement serotypes have emerged. Serogroups 15 and 33 have emerged as nonvaccine serotypes causing invasive disease. We describe the clinical characteristics of children with infections caused by these serogroups and determined the genetic relationship of the strains.The United States Pediatric Multicenter Pneumococcal Surveillance Group has prospectively identified children with pneumococcal infections since 1993. Charts were reviewed retrospectively, isolates were serogrouped and serotyped and randomly selected strains were fingerprinted with the use of pulsed field gel electrophoresis. Selected strains were further characterized by multilocus sequence typing.Between January 1994 and December 2004, 103 children had pneumococcal disease caused by serogroup 15, and 40 children had infections caused by serogroup 33. There was an increase from a mean of 7 cases per year for serogroup 15 in the prevaccine period to 14 cases per year in the postvaccine period and from 2 cases per year for serogroup 33 to 7 cases per year in the same periods. Isolates were susceptible to penicillin and ceftriaxone in both periods. A predominant clone was found in each serogroup representing 60% (30 of 50) of serogroup 15 strains and 83% (24 of 29) of the serotype 33F strains. The serogroup 15 clone comprised strains of serotypes 15B and 15C, whereas the 33 clone contained only serotype 33F strains. One isolate from each of the 15 and 33 clones was characterized by multilocus sequence typing and were found to be ST199 and 100, respectively.Pneumococcal disease in children caused by penicillin-susceptible clones of serogroups 15 and 33 is increasing in the United States. Clinicians should consider replacement serotypes when encountered with invasive pneumococcal disease in vaccinated children.