Background: Spirometry is the gold standard for assessing airway function for clinical studies; however, obtaining high quality data in young children remains challenging. Since the forced oscillation technique (FOT) requires less subject cooperations, there has been increasing interest in FOT, particularly in young children. We evaluated whether spirometry and FOT in young children provides comparable ability to detect a treatment effect. Methods: We recently reported in a randomized controlled trial that vitamin C compared to placebo treatment of mothers who smoked during pregnancy (MSDP) results in the offspring having significantly higher forced expiratory flows at 5-years of age, as well as significantly less wheeze at 4-6 years of age. In these same offspring, we also measured FOT at 8-Hz impedance at 3, 4, and 5 years of age. Results: Although spirometry demonstrated significantly increased forced expiratory flows (FEFs) in the vitamin C compared to placebo treatment group at 5-years of age (p < 0.001), we were not able to detect a similar treatment effect using FOT impedance. Conclusions: It may be challenging to obtain technically successful spirometry in pre-school children; however, forced expiratory flows may provide a better outcome than single frequency FOT impedance to assess improvements in airway function in these young subjects.