Defensins are highly conserved peptides with antimicrobial and immunomodulatory functions. Due to their chemotactic properties on mononuclear cells, including dendritic cells and macrophages, defensins may contribute to granuloma formation in Wegener's granulomatosis (WG). In order to explore whether these peptides might be involved in WG pathogenesis, sera of patients were screened to detect altered defensin levels. For this purpose, serum and EDTA-blood of patients with WG (n = 17; aged 54.8 ± 15.5 years) and age- and sex-matched healthy controls (n = 24; aged 55.5 ± 16.8 years) were collected. Levels of neutrophil α-defensins (human neutrophil peptides, HNP) and β-defensin (hBD) 2 and 3 in serum were measured by ELISA. By this means, WG patients displayed higher serum levels of hBD2 and HNP when compared to controls. Furthermore, serum hBD2 was raised in patients with meningeal granulomas (n = 4) or in those undergoing treatment with cyclophosphamide (n = 4). In order to detect whether increased gene expression in polymorphonuclear cells is responsible for the elevated defensin levels, real-time polymerase chain reaction with gene-specific primers was performed. Expression of specific mRNA in polymorphonuclear cells was observed for HNP only, but did not parallel HNP serum levels, suggesting that degranulation rather than increased gene expression may be responsible for increased HNP serum levels in WG. In conclusion, elevated serum levels of HNP and hBD2 in WG patients suggest a role for both defensins in WG pathogenesis.