ABSTRACTLight’s criteria is the standard for determining the etiology of pleural effusions. Test characteristics of Light’s criteria varies in different populations, and Light’s criteria may misclassify effusions in patients with impaired immunity such as in neutropenia. This study evaluates the test characteristics of Light’s criteria and other clinically available pleural fluid tests in a cohort of patients with neutropenia. Cases were defined as a thoracentesis performed with an absolute neutrophil count of less than 1000 cells/µl documented at least 24 hours prior to the procedure. The etiology of the effusion was adjudicated by independent review of the case data and hospital course by two board certified pulmonologists. Categories for final diagnosis included exudate due to infection, exudate due to malignancy, exudate due to other, and transudate. A total of 83 thoracenteses from 80 patients were identified. Comorbidities included hematologic and solid tumor malignancies, recipients of allogeneic stem cell and solid organ transplants, heart failure, chronic kidney disease, and decompensated cirrhosis. Light’s criteria had a sensitivity of 92% and a specificity of 55% for identifying exudates, LR+ 2.07 and LR-0.14. A pleural fluid protein value of >2.9 g/dl had a sensitivity of 42% and a specificity of 96%, LR+11.12 and LR-0.61. When comparing exudative effusions, the percentage of neutrophils in the pleural fluid was significantly higher in infection, despite peripheral neutropenia. Together these results show a reduced specificity of Light’s criteria in neutropenia, and underscore the complexity of pleural effusions in this setting.