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South Africa introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in 2009 and PCV13 in 2011. The etiology and incidence of childhood empyema in an 8-year period overlapping the introduction of PCV was investigated.Children younger than 12 years admitted with empyema at a tertiary pediatric hospital in Cape Town, South Africa, from December 2006 to December 2011 (cohort A) and January 2012 to December 2014 (cohort B) were investigated. Pathogens were identified by culture of pleural fluid and blood. In addition, polymerase chain reaction targeting bacterial pathogens and Streptococcus pneumoniae serotypes was conducted on pleural fluid in a subset of patients enrolled 2009–2011.Cohort A: 142 children were prospectively enrolled, with a median age of 17 months (interquartile range 8–43). Most (92%) children were unimmunized with PCV. S. pneumoniae and Staphylococcus aureus were the most common culture-identified pathogens (each 25 of 142; 18%); polymerase chain reaction of pleural fluid increased yield of S. pneumoniae detection by 31% [26 of 54 (48%) vs. 9 of 54 (17%), P < 0.001]. Serotypes were identified for 24 of 26 (92%) patients with S. pneumoniae, of which 22 of 24 (92%) were included in PCV13. Cohort B: 22 patients were retrospectively identified. No pathogen was found in 12 of 22 (54.5%) patients and S. pneumoniae in 1 patient (4.5%). Empyema incidence declined by 50% in cohort B compared with that of cohort A (4.2 vs. 10.4 cases per 1000 pneumonia admissions; risk ratio: 0.5; 95% confidence incidence: 0.3–0.7).S. pneumoniae is the commonest cause of childhood empyema in South Africa. PCV has been highly effective at reducing empyema incidence in South African children.