Background: Compartment analysis (CA) based on nitrogen multiple-breath washout (N₂MBW) has been shown to allow the assessment of specific volume and ventilation of faster- and slower-ventilating lung compartments of the lung in adults with cystic fibrosis (CF). The aim of this study was to extend previous findings into the pediatric age range. Methods: Cross-sectional multicenter observational study in children with CF and healthy controls (HC) was done with the assessment of N₂MBW and spirometry. A two-lung compartment model-based analysis (CA) was used to estimate size and function of faster- and slower-ventilating lung compartments from N₂MBW. Results: A total of 125 children with CF and 177 HC, median age 10.8 (range, 2.8-18.9) years, were included in the analysis. CA could be calculated in 66 (53%) children with CF compared with 48 (27%) HC (P <.0001). The proportion of the slower-ventilating lung compartment was significantly smaller in children with CF (53.5%; 95% confidence interval [CI]: 51.9%-55.7%) compared with HC (62.2%; 95% CI: 59.0%-65.0%) The regional specific ventilation of the slower compartment (rV_T,slow/rFRC,slow, %) was significantly lower in children with CF (4.9%; 95% CI: 4.5-5.9) compared with HC (9.7%, 95% CI: 9.2-10.9), and showed inverse correlation to lung clearance index (r² = −.65; P <.0001), S_acin × VT (r² = −.36; P =.003) and S_cond × VT (r² = −.51; P <.0001). There was no significant difference in pulmonary parameters between children with CF with and without feasible CA. Conclusion: CA is less feasible in children than in adults and correlated to other MBW parameters. The clinical value of CA is still unclear and is yet to be established.