A parallel, randomized, double-blind study was performed in 30 healthy subjects to investigate the effects on the nasal mucosa of a 1-month treatment with nasal sprays. Ten subjects received oxymetazoline nasal spray; 10 subjects used a nasal spray containing the preservative benzalkonium chloride, and the others were treated with a placebo nasal spray. The three variables that were studied --nasal mucosal swelling, symptom scores, and nasal reactivity-- were estimated by histamine challenge before and after 28 days of treatment. Rhinostereometry was used to measure nasal mucosal swelling and nasal reactivity. After 28 days of use, benzalkonium chloride spray alone induced an increase in nasal mucosal swelling. At the end of the month, the score for nasal stuffiness was significantly higher for the group treated with oxymetazoline than for those treated with benzalkonium chloride. Oxymetazoline nasal spray induced a pronounced increase in nasal reactivity, which was significantly greater than that induced in the placebo group. Long-term use of placebo and benzalkonium chloride nasal sprays also caused an increase in nasal reactivity, but not to the same extent as with the nasal sprays containing oxymetazoline. The authors concluded that long-term use of oxymetazoline induces a sensation of nasal stuffiness, which may be due to unconscious exaggeration of the degree of nasal stuffiness, induced nasal hyperreactivity, or a combination of both. These factors are probably the main reasons for the prolonged use of nasal decongestive sprays and the development of rhinitis medicamentosa. Benzalkonium chloride induces mucosal swelling, which explains why the presence of this preservative in a decongestant spray aggravates rhinitis medicamentosa.