BACKGROUND: Despite increasing incidence and morbidity, little evidence exists to inform the best management approach in childhood empyema. AIM: To compare chest drain with intrapleural urokinase and primary video-assisted thoracoscopic surgery (VATS) for the treatment of childhood empyema. METHODS: Children were prospectively randomized to receive either percutaneous chest drain with intrapleural urokinase or primary VATS. The primary outcome was the number of hospital days after intervention. Secondary end points were number of chest drain days, total hospital stay, failure rate, radiologic outcome at 6 mo, and total treatment costs. RESULTS: Sixty children were recruited. The two groups were well matched for demographics; baseline characteristics; and hematologic, biochemical, and bacteriologic parameters. No significant difference was found in length of hospital stay after intervention between the two groups: VATS (median [range], 6 [3-16] d) versus urokinase (6 [4-25] d) (p = 0.311; 95% confidence interval, -2 to 1). No difference was demonstrated in total hospital stay: VATS versus urokinase (8 [4-17] d and 7 [4-25] d) (p = 0.645); failure rate: 5 (16.6%); and radiologic outcome at 6 mo after intervention in both groups. The mean (median) treatment costs of patients in the urokinase arm US dollars 9,127 (US dollars 6,914) were significantly lower than those for the VATS arm US dollars 11,379 (US dollars 10,146) (p < 0.001). CONCLUSIONS: There is no difference in clinical outcome between intrapleural urokinase and VATS for the treatment of childhood empyema. Urokinase is a more economic treatment option compared with VATS and should be the primary treatment of choice. This study provides an evidence base to guide the management of childhood empyema.