The aim of this study was to evaluate histologic changes after long-term administration of the topical nasal decongestants phenylephrine and oxymetazoline. Ninety healthy rabbits were divided into 3 groups for topical administration for 1 week, 2 weeks, and 4 weeks. Each group was subdivided into 3 subgroups by topical administration of phenylephrine. oxymetazoline, and physiologic saline as controls. Each study group thus consisted of 10 rabbits. Phenylephrine was administered by 2 puffs in the left nostril 5 times daily and oxymetazoline by 2 puffs twice a day using metered sprayers giving 0.10 ml in each puff with a dosage used in clinical practice. For statistical significance the Kolmogorov-Smirnov test was used. Light and electron microscopic examination were performed after obtaining nasal respiratory mucosa from the nasal septum of the rabbits. Administration of phenylephrine and oxymetazoline for more than 2 weeks caused histologic changes including ciliary loss, epithelial ulceration, inflammatory cell infiltration and subepithelial edema, and the changes were more pronounced with increasing administration duration of the decongestants. Ciliary loss was prominent in the 4-week phenylephrine and oxymetazoline groups. There were significantly severer changes in the morphologic variables in the decongestant groups compared with the control group according to administration duration (p < 0.05). Dilatation or vacuolization of mitochondria and endoplasmic reticula and vesicles ill the cytoplasm were observed in the 2- and 4-week phenylephrine groups as well as the 2- and 4-week oxymetazoline groups. Mild widening of the intercellular space was observed in the 4-week phenylephrine group. Purulent maxillary sinusitis developed in 6 of 10 rabbits treated for 4 weeks with phenylephrine. The results of this study suggest that the administration of decongestants may cause ciliary loss with subsequent inflammatory changes in the nasal respiratory mucosa.