Background: The fractional concentration of exhaled nitric oxide (FeNO) is a noninvasive marker for airway inflammation but requires further study in preschool-aged children to determine its clinical relevance. Objective: To determine whether the risk of respiratory tract illnesses (RTIs), disease burden, and atopic features are related to FeNO in preschool-aged children with moderate-to-severe intermittent wheezing. Methods: We determined FeNO using the off-line tidal breathing technique in 89 children, aged 12 to 59 months, with moderate-to-severe intermittent wheezing. The risk of RTI was determined by comparing participants with a baseline FeNO of greater than the 75th percentile (24.4 ppb) with those with a baseline FeNO at the 75th percentile or lower using Cox regression analysis. Results: The risk of RTI was significantly higher in children with an FeNO of greater than 24.4 ppb relative to those with lower FeNO values (adjusted relative risk, 3.80; 95% confidence interval, 1.74-8.22; P < .001). FeNO levels of greater than 24.4 ppb were associated with more positive skin test results to aeroallergens (P = .03) but not with other atopic characteristics or historic parameters of illness burden. Conclusions: An elevated FeNO in preschool-aged children with moderate-to-severe intermittent wheezing was associated with an increased risk of RTI during a 1-year follow-up. In addition, a higher FeNO was associated with aeroallergen sensitization.