Background. Information about the burden of invasive pneumococcal disease among children in Pakistan is limited. Methods. Surveillance of bacterial meningitis among children aged <5 years was set up at 18 hospitals in southern Pakistan that fulfilled the following criteria: (1) >30 pediatric admissions weekly, (2) skilled personnel to perform lumbar punctures, and (3) close proximity to an Aga Khan University Hospital laboratory collection point. Results. A total of 2690 children were admitted to the hospital with suspected acute bacterial meningitis, and 2646 (98%) underwent lumbar puncture. Of the 2646 cerebrospinal fluid specimens obtained, 412 (16%) were purulent, and pathogens were detected by culture or latex agglutination testing in 83 (20.1%) of the purulent specimens. Of the 83 isolates detected, 48 (57.8%) were Haemophilus influenzae type b, 32 (38.5%) were Streptococcus pneumoniae, and 3 (3.6%) were Neisseria meningiditis. Overall, 81% of the pathogens detected were from children aged <1 year. More than 50% of families reported definite prior antimicrobial use. The minimum detected incidence rates of purulent meningitis in Hyderabad were 112 cases per 100,000 children aged <1 year and 45.3 cases per 100,000 children aged <5 years. After adjustment for limitations in access to care and the low sensitivity of cerebrospinal fluid culture, the adjusted incidence rates of pneumococcal meningitis were 81 cases per 100,000 children aged <1 year (95% confidence interval, 26.2-190.5 cases per 100,000) and 20 cases per 100,000 children aged <5 years (95% confidence interval, 7.3-43.7 cases per 100,000). Of the 32 children with pneumococcal meningitis, 8 (25%) died during hospitalization. Conclusions. Our surveillance system detected a substantial burden of purulent meningitis among infants and children in southern Pakistan. H. influenzae type b and S. pneumoniae accounted for >90% of detected pathogens. The use of vaccines against these 2 pathogens could prevent a substantial portion of disease and deaths in Pakistan.