It is not known whether the progressive airway changes in cystic fibrosis (CF) are all secondary to infection and inflammation. The CF mouse nose shares electrophysiological and cellular properties with human CF airway epithelium. In the present work, we tested the hypothesis that structural abnormalities in the nasal mucosa of CF mice develop independent of infection and inflammation. We performed nasal lavage and subsequent serial coronal section through the nasal tissue of adult CF (mutations Cftr^TgHm1G551D and Cftr^tm1Unc-TgN^(FABPCFTR)) and wild type mice raised under normal housing conditions. Nasal tissue was also obtained from day 17 embryos and newborn pups. Detailed histological examination of the respiratory and olfactory epithelium within the nasal cavity was performed. Bacterial culture, cell count and Macrophage Inflammatory Protein-2 (MIP-2) concentration were assessed in nasal lavage fluid. Significantly thickened respiratory epithelium and increased mucous cell density was found in adult CF mice of both mutations compared to wild type animals. In contrast, the olfactory epithelium was thinner, with a decreased cell density. Areas of lymphoid aggregates were found in CF, but in not in non-CF mice. There were no differences in bacterial growth, cell count or MIP-2 concentrations. No genotype differences were observed in the embryonic or newborn periods. There are significant histological changes in the nasal mucosa of adult CF mice, not associated with increased lumenal inflammation or bacterial content, and which are not present perinatally. These may be novel therapeutic targets.