Nitric oxide (NO) is known to play a role in the non-specific host defence mechanism. Furthermore, it has been proposed that NO may be important in respiratory defence against the viruses which cause the common cold. Indeed, elevated NO levels have previously been observed in orally expired air during upper respiratory tract infection (URTI). We wanted to investigate further the role of NO in the host response to URTI. Total nasal airway resistance (tNAR) and nasal NO levels were obtained during symptomatic URTI in 97 subjects. Of these, 80 received treatment with either oxymetazoline or a placebo spray. Post-treatment tNAR and NO levels were obtained 60 min after treatment. Measurements of NO were also repeated 4-6 weeks later, when subjects were healthy, (n = 82). NO levels were measured using a chemiluminescence gas analyser whilst tNAR was measured using posterior rhinomanometry. The mean pre-treatment NO level (1063 ± 541 ppb) was shown to be reduced significantly after treatment with oxymetazoline (827 ± 373ppb), p < 0.0001. The mean pre-treatment tNAR, 0.42 Pa cm^-3 sec^-1, was also reduced significantly to 0.21 Pa cm^-1 sec' (p < 0.001) after treatment with oxymetazoline. There was no significant correlation between the change in NO levels and change in tNAR following treatment with oxymetazoline (p, corrected for ties = 0.011, p = 0.98). No significant difference was found between NO levels obtained during URTI (1130 ± 444 ppb) when compared to values obtained when healthy (1197 ± 361 ppb), p =0.25. These results demonstrate that treatment with a topical nasal decongestant spray causes a reduction in nasal NO levels. We propose that this occurs as an indirect consequence of the vasoconstrictor actions of oxymetazoline. Since no change in NO levels was observed during URTI, we propose that the NO synthase responsible for NO production in the nose responds in a different manner to that in the lungs.