Background. Childhood pneumonia is common in all countries, and empyema is one of the commonest complications. The role of routine intrapleural fibrinolytics in the management of childhood empyema is not well established in low- and middle-income countries.Methods. We did a prospective observational study of children sequentially hospitalised with empyema between December 2006 and December 2011 in South Africa (SA). Intrapleural tissue plasminogen activator (TPA), administered according to a standard protocol, was introduced in September 2009. Outcomes in children treated with TPA after 2009 were compared with the historical cohort not treated with TPA who met the treatment criteria.Results. One hundred and forty-two children with empyema, median age 17 months (interquartile range 8 - 43), were admitted during the study period. Excluding children who did not have a chest tube inserted and those in whom fibrinolysis was contraindicated, there were 99 patients, 52 of whom received fibrinolytics. Clinical characteristics and empyema aetiology were similar in those who received fibrinolysis and those who did not. Eighteen children (38.3%) not treated with TPA required surgery v. 5 (9.6%) treated with TPA (relative risk 0.25; 95% confidence interval 0.1 - 0.6). The median duration of hospitalisation was similar in both groups. Complications occurred rarely and with a similar incidence in both groups. In-hospital mortality was low, with two deaths in each group.Conclusion. Intrapleural TPA resulted in a four-fold reduction in surgery. Fibrinolytics should be used for management of empyema in children in SA