Whether nasal congestion promotes obstructive sleep apnea is controversial. Therefore, we performed a randomized placebo-controlled cross-over trial on the effects of topical nasal decongestion in patients with obstructive sleep apnea syndrome (OSA) and nasal congestion. Twelve OSA patients with chronic nasal congestion (mean ± SD age 49.1 ± 11.1 years, apnea/hypopnea index 32.6 ± 24.5/h) were treated with nasal xylometazoline or placebo for 1 week each. At the end of treatment periods, polysomnography including monitoring of nasal conductance by an unobtrusive technique, vigilance by the OSLER test, and symptom scores were assessed. Data from xylometazoline and placebo treatments were compared. Mean nocturnal nasal conductance on xylometazoline was significantly higher than on placebo (8.6 ± 5.3 versus 6.3 ± 5.8 mL s−1Pa−1, P < 0.05) but the apnea/hypopnea index was similar (29.3 ± 32.5/h versus 33.2 ± 32.8/h, P = NS). However, 30–210 min after application of xylometazoline, at the time of the maximal pharmacologic effect, the apnea/hypopnea index was slightly reduced (27.3 ± 30.5/h versus 33.2 ± 33.9/h, P < 0.05). Xylometazoline did not alter sleep quality, sleep resistance time (33.6 ± 8.8 versus 33.4 ± 10.1 min, P = NS) and subjective sleepiness (Epworth score 10.5 ± 3.8 versus 11.8 ± 4.4, P = NS). The reduced apnea/hypopnea index during maximal nasal decongestion by xylometazoline suggests a pathophysiologic link but the efficacy of nasal decongestion was not sufficient to provide a clinically substantial improvement of OSA. ClinicalTrials.gov Identifier is NTC006030474.