Leukocytosis in association with malignancy has been well described, but the cause is not known. One potential explanation is production of a colony-stimulating factor by the tumor, and this has been demonstrated in vitro. The authors report two patients with lung cancer, leukocytosis, and eosinophilia. The pleural fluid of both patients contained malignant cells and biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF), as demonstrated by radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and colony-forming unit-granulocyte-macrophage (CFU-GM) assay. To determine whether GM-CSF is normally detectable in pleural fluid, the authors performed assays on an additional 11 patients with pleural effusions of various origins but without peripheral blood leukocytosis and eosinophilia; only 1 patient had a detectable level of GM-CSF (i.e., greater than or equal to 0.1 ng/ml). Because GM-CSF usually is not present in pleural fluid, the authors postulate that the high levels of GM-CSF found in the pleural fluid of these two patients was produced by their tumors, and production of GM-CSF by their lung cancers likely caused the leukocytosis with eosinophilia.