Background Multiple-breath washout (MBW) is used to calculate a measure of ventilation heterogeneity, the lung clearance index (LCI), and requires tidal breathing until a previously inspired tracer gas concentration falls below 1/40th of the initial value, an arbitrary threshold. LCI is usually performed in triplicate, each taking 4–8 min to complete which may be taxing, particularly in young children and those with marked airflow obstruction. Shortened LCI is of interest since a reduction in the test time may increase feasibility and improve the clinical applicability of the measurement. We hypothesised that LCI measurements could be reliably shortened. We also investigated whether shortened MBW was responsive to an intervention. Patients and methods We calculated LCI from a fixed time point, and from a fixed number of breaths, as well as LCI and 25% (LCI0.25), 50% (LCI0.5) and 75% (LCI0.75) of 1/40th of the initial concentration of tracer gas (LCIstd) and the time saved, in children aged 6–16 years with asthma (n = 21), cystic fibrosis (CF, n = 20) and primary ciliary dyskinesia (PCD, n = 19), and healthy controls (n = 17), aged 3–18 years. Shortened LCI was also calculated in 29 asthmatic children pre and one month post one intra-muscular triamcinolone injection, part of our clinical severe asthma protocol. Results Calculating shortened LCI from a fixed washout time or breath number was not reliable. However, all shortened LCI measurements from initial gas concentration correlated significantly with LCIstd in each disease group. LCI0.5 presented a balance between correlation with LCIstd (see figure) and time-saving. Mean proportion of time saved per washout, using LCI0.5, was 27% (asthma), 28% (CF) and 31% (PCD). Furthermore, LCI0.5 was significantly reduced after triamcinolone in children with severe asthma (mean LCI0.5 pre, 5.5 and 5.1 post triamcinolone, p = 0.02), and the change was similar to that demonstrated using LCIstd (mean LCIstd pre, 7.8 and post 7.0, p = 0.001). Conclusion We show for the first time that LCI measurements can be shortened without loss of information in school-children with asthma, CF and PCD. LCI0.5 was the optimal surrogate measure for LCIstd when proportion of time saved, correlation with LCIstd and change following an intervention were considered.