According to population-based invasive pneumococcal surveillance in the United States during 2007, 898 (26%) of 3,511 isolates were penicillin nonsusceptible. Non-7-valent pneumococcal conjugate vaccine (PCV7) serotypes other than 19A accounted for 40% of these penicillin-nonsusceptible isolates; of these, serotypes 15A (11%), 23A (8%), 35B (8%), and 6C (5%) were most common (cumulatively 32% of penicillin-nonsusceptible isolates). Each except 6C represented a single serotype and clonal complex combination that predated the introduction of PCV7. We evaluated the genetic characteristics and nonsusceptibility to penicillin of non- PCV7 serotypes, and we found increased proportions of specific penicillin-nonsusceptible clones in serotypes 15A, 23A, 35B, and 6C, which potentially indicates a basic change of population structure within these individual serotypes.