Background Calgranulin C (S100A12) is an innate immune peptide at the air-mucosal interface associated with neutrophil involvement, which when overexpressed has been implicated as a biomarker of inflammatory diseases. Decreased epithelial expression of certain innate immune peptides has been reported in chronic rhinosinusitis (CRS). We hypothesized that S100A12 is differentially expressed in the sinonasal mucosa of patients with CRS compared to controls and that S100A12 is a potential biomarker of CRS-specific quality of life (QOL) and disease severity. Methods A prospective observational study was conducted which included 70 patients: 17 controls, 28 having CRS without (CRSsNP), and 25 with (CRSwNP) nasal polyps. The expression of S100A12 and human neutrophil elastase (HNE) was assessed in the anterior ethmoid tissues from all patients using enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) analyses. Disease-specific QOL (Rhinosinusitis Disability Index) and disease severity (computed tomography [CT] and endoscopy) were evaluated and correlated to the expression levels of S100A12. Results S100A12 and HNE were significantly elevated in patients with CRSsNP compared to normal controls ( P < .05 and P < .001, respectively) and patients with CRSwNP ( P < .05 and P < .001, respectively), as measured by ELISA and IHC analyses. Patients with CRS exhibited worse CRS-specific disease severity compared to normal controls ( P < .05), and the increased protein levels of S100A12 were significantly correlated to disease severity, represented by CT scores ( P < .05). Conclusions S100A12 is differentially expressed in CRS subtypes and is significantly elevated in patients with CRSsNP and associated with CRS-specific disease severity.