Rationale: Nitrogen multiple-breath washout (N2 MBW) is a promising tool for assessing early lung damage in children with chronic obstructive pulmonary disease, but it can be a time-consuming procedure. We compared alternative test-shortening endpoints with the most commonly reported N2 MBW outcome, the lung clearance index, calculated as lung volume turnovers required to reach 2.5% of the starting N2 concentration (LCI2.5). Methods: Cross-sectional study of triplicate N2 MBW measurements obtained in cystic fibrosis (CF) patients (N = 60), primary ciliary dyskinesia (PCD) patients (N = 28), and matched healthy controls (N = 48) aged 5–18 years. Bland–Altman analysis was used to compare LCI2.5 with earlier LCI endpoints (3%, 4%, 5%, 7%, and 9% of starting N2 concentration), Cn@TO6 (defined as % of N2 starting concentration when reaching six lung volume turnovers), and LCI derived from only two N2 MBW runs in each session. N2 MBW endpoints were analyzed as z-scores calculated from healthy controls. Results: In PCD, Cn@TO6 and LCI2.5 exhibited similar values (mean [95%CI] difference: 0.33 [−0.24; 0.90] z-scores), reducing the test duration by one-third (5.4 min; 95%CI: 4.0; 6.8). All other tested alternative endpoints exhibited increasing disagreement with increasing LCI2.5. With an average reduction in test duration of 40%, LCI2.5 derived from two runs exhibited good agreement in all children. Conclusions: Cn@TO6 may be suggested as a potential test-shortening endpoint in school children with PCD. In CF, early test termination may reduce measurement power with advancing pulmonary disease, suggesting differences in underlying pathophysiology. Two technically acceptable N2 MBW runs may be sufficient in school children irrespective of diagnosis with CF or PCD. Pediatr Pulmonol. 2016;51:624–632. © 2015 Wiley Periodicals, Inc.