Conclusions: Our results indicate that chronic rhinosinusitis without nasal polyps (CRSsNP) is characterized by the down-regulation of a Toll-like receptor (TLR)-mediated signaling pathway and such a deficiency within the innate immune system may contribute to the inflammatory process of CRSsNP. In contrast, the inflammatory process found in CRS with nasal polyps (CRSwNP) is characterized by an excessively activated TLR-mediated signaling pathway, which may contribute to the formation of nasal polyps. This study suggests that the pathophysiologic mechanism of CRSsNP and CRSwNP is different. Objective: The nasal mucosa expresses a variety of TLRs that serve in recognizing microorganisms. We investigated the gene expression of a TLR-mediated signaling pathway within two distinctive patient subgroups: CRSwNP and CRSsNP. Methods: Nasal mucosal tissue was obtained from 78 subjects with CRS and 23 control subjects. qRT-PCR and immunohistochemistry were used to investigate tissues for the expression of TLR2, TLR4, TLR7, their downstream signaling components, MyD88 and TRIF, and associated cytokines, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10. Results: TLR2, TLR4, TLR7, and IL-4 were significantly increased in CRSwNP patients when compared with either CRSsNP patients or control subjects, whereas TLR4 and TLR7, and downstream MyD88 were significantly decreased in CRSsNP patients versus patients from CRSwNP and control subjects.