This study demonstrates, for the first time, that prolonged unilateral breathing can be harmful to the adult olfactory epithelium. Mice at least 5 months old had one naris closed by cautery and suture. These were divided into 5 groups of 10 mice which had unilateral naris closure for 1, 3, 6, 8 or 12 weeks. A control group of 10 mice was untreated. Variables that were assessed included the thicknesses and numbers of cells spanning olfactory epithelia in hematoxylin and eosin stained paraffin sections. Olfactory marker protein (OMP) immunohistochemistry was used to further visualize the differential impact of naris closure on the two sides of the nose. Unilateral naris closure for 6 weeks or longer caused dramatic losses of olfactory receptor cells in the rostral third of the open-side olfactory epithelia, but did not affect numbers of cells in caudal regions or on the closed sides. The thicknesses of the open and closed-side olfactory epithelia were significantly different for only the 8-week closure group. In most mice with unilateral naris closure for longer than 6 weeks there was little or no staining of the olfactory receptor neurons or their axon bundles for OMP in the affected regions of the open side.