Background. Nine- and 11-valent pneumococcal conjugate vaccines under development may control pediatric pneumococcal disease in non-industrialized countries. Because these vaccines are expensive, population-based surveillance of pneumococcal disease in children <36 months of age was undertaken in Santiago, Chile to provide health authorities with reliable data on the burden of invasive pneumococcal disease and causative serotypes, including those in outpatients with high fever. Methods. Automated blood culture machines were introduced into 9 hospitals that admit 85% of all hospitalized children in Santiago. Acutely ill pediatric febrile ambulatory patients are attended at 8 emergency rooms (ERs) and 36 urgent primary care services. After a 12-month pilot study in 3 ERs, health authorities collected blood cultures from children <36 months of age with high fever seen in the ER as standard practice. Streptococcus pneumoniae isolates were serotyped. Results. Blood cultures of 18 (1.2%) of 1503 outpatients 6 to 35 months of age with high fever in the pilot study yielded S. pneumoniae. In the ensuing 24 months 236 children <36 months old were hospitalized with invasive pneumococcal disease (incidence, 33.9 cases/105 children), and 188 bacteremias were detected among ambulatory ER patients with high fever (incidence, 27.0 cases/105 children). Although serotypes were similar among hospitalized and ambulatory cases (except 18C, which was more common in the latter), case fatality was 9.5% in hospitalized (21 of 236) vs. 0% in ambulatory cases (0 of 188) (P = <0.0001). High level resistance to penicillin (25.8% vs. 10.1%) and cefotaxime (19.5% vs. 6.2%) was observed more often among pneumococcal isolates from hospitalized than among ambulatory cases (P < 0.001). Conclusions. ER surveillance detected approximately one case of pneumococcal bacteremia among febrile ambulatory patients for each hospitalized invasive case. Because 71% of cases were caused by vaccine serotypes (and 87% by vaccine serogroups), 9- and 11-valent pneumococcal conjugate vaccines could prevent most invasive pediatric pneumococcal disease in Chile.