Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a recurrent, benign, extensively proliferating disease that is triggered by inflammation. The signaling pathways in sinusitis and the regulation by intracellular signaling peptides and proteins are not fully understood. Signal transducer and activator of transcription (STAT) 5a and STAT5b are two closely related phosphokinases involved in the regulation of diverse cellular functions, including proliferation and apoptosis. Objective: The objective of the study was to investigate the expression, activation, and distribution of STAT5 Transcription factor in CRSwNP. Methods: We studied these transcription factors in tissue samples of nasal polyps and inferior turbinates from a total of 35 patients with CRSwNP and compared them with healthy nasal mucosa. The samples were analyzed by using a DNA microarray, quantitative real-time polymerase chain reaction, a protein array, immunoblot, immunoprecipitation and immunohistochemistry. Results: We found equivalent overall expression of STAT5a in all tissue types. We observed an increase in the expression of STAT5b protein in both polyps and turbinates of patients with CRSwNP. In addition, STAT5b, but not STAT5a, was activated by phosphorylation in nasal polyps. Phosphorylated STAT5a/b was not detectable in the epithelium of turbinates from either patients with CRSwNP or patients with healthy mucosa, but it was clearly expressed in the epithelium of nasal polyps. Conclusion: Analysis of these data indicates distinct expression and activation of STAT5a and STAT5b in nasal polyps, particularly the activation of STAT5b. It is possible that STAT5b may contribute to the development of nasal polyps.