Histones have been associated with human diseases. However, the implication of extranuclear histone proteins and their potential mechanism in the pathophysiology of chronic rhinosinusitis (CRS) have not been thoroughly investigated. This study was designed to evaluate the role of histones in patients with CRS by comparing histone expression between patients and controls. Nasal polyp (NP) tissues were obtained, and their comprehensive gene expression profiles were investigated by microarray analysis. Differences in expression were verified by reverse transcriptase polymerase chain reaction and immunohistochemical staining. Cell culture and flow cytometry were used to evaluate the role of histones in the pathogenesis of polyps. Significant differences in the microarray analysis were observed between the patient and control groups (P < 0.01). It was found by flow cytometry that the histone (H2BK) can promote cell apoptosis in NPs. Our results indicate that reduced expression of H2BK may contribute to the imbalance process of cell proliferation and apoptosis in CRS with NP.