Streptococcus pneumoniae (pneumococcus) is a leading cause of otitis, sinusitis, pneumonia, and meningitis worldwide. Treatment of the most serious type of pneumococcal infection, invasive pneumococcal disease (IPD),* is complicated by antimicrobial resistance. Widespread introduction in 2000 of heptavalent pneumococcal conjugate vaccine (PCV7) against serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F resulted in a decline in antimicrobial-nonsusceptible IPD in the United States1,2, including in Massachusetts.3 However, development of antimicrobial resistance in serotypes not covered by PCV7 is a growing concern1,4. In Massachusetts during 2001-2006, IPD surveillance identified an increased number of cases in children caused by pneumococcal serotypes (most notably 19A) not covered by PCV7 and an associated increase in antimicrobial resistance among these isolates. This report examines these trends and clinical characteristics of Massachusetts patients with antimicrobial-nonsusceptible, non–PCV7-type IPD. The findings indicated that, despite increases in incidence of antimicrobial-nonsusceptible IPD, overall rates of IPD remained stable during 2001-2006. In addition, persons with IPD caused by antimicrobial-nonsusceptible S. pneumoniae had clinical outcomes comparable to persons with IPD caused by antimicrobial-susceptible serotypes. Although PCV7 is effective in preventing IPD, these results confirm that antimicrobial resistance among serotypes not covered by PCV7 remains a concern.