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The microbiological diagnosis of pleural effusion is largely based on classical microbiology methods, but these methods have a high rate of false negative results. Some previous studies have shown improved diagnostic performance for pathogens such as S. pneumoniae using molecular biology methods. We present the use of a Multiplex-PCR platform (BIOFIRE® FILMARRAY® Pneumonia Panel) for the etiological diagnosis of pleural effusion in pediatric pneumonia. We present a case series of 17 pleural fluid samples that were processed by culture-based microbiology and molecular biology methods. Microbiological isolation was successful in 4 cases (25%) through traditional culture methods. In contrast, the molecular biology panels allowed for detection in 16 out of 17 cases (94%). The results from these panels led to a change in management for 9 out of the 17 cases (52%). This study found an increase in etiological diagnosis in complicated pneumonia in children using molecular biology methods, which led to a significant change in patient management.