OBJECTIVE Because 7-valent pneumococcal conjugate vaccine (PCV7) is highly efficacious, pneumococcal infections in vaccinated children raise concerns about immunologic disorders. We characterized a case series of US children in whom invasive pneumococcal infections developed despite vaccination. METHODS We reviewed invasive (sterile site) pneumococcal infections in children aged <5 years who had received > or =1 PCV7 dose as identified from October 2001 to February 2004 through national passive surveillance and the Centers for Disease Control and Prevention's Active Bacterial Core surveillance. Vaccine serotype infections were considered breakthrough cases; the subset of breakthrough cases occurring in children who completed an age-appropriate vaccination series were considered PCV7 failures. RESULTS We identified 753 invasive infections; 155 infections (21%) were breakthrough cases, predominantly caused by serotypes 6B (n = 50, 32%) and 19F (n = 45, 29%). The proportion of breakthrough cases decreased with the increasing number of PCV7 doses received (P < .001, Chi(2) for linear trend). Children with co-morbid conditions accounted for 31% of breakthrough infections. Twenty-seven cases (4%) were classified as vaccine failures. Most failures (71%) occurred in children who were vaccinated according to catch-up schedules; 37% had co-morbid conditions. CONCLUSIONS Invasive pneumococcal infections identified in vaccinated U.S. children were primarily caused by disease resulting from serotypes not covered with PCV7, rather than failure of the vaccine. Incomplete vaccination and co-morbid conditions likely contribute to breakthrough vaccine-type pneumococcal infections.