Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF6 MBW commonly viewed as the reference method. The use of N2 MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N2  signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF6 and N2 MBW,corrected-such as tidal volume reduction during N2 washout with pure O2 . This was a longitudinal multicenter cohort study. SF6 MBW and N2 MBW were performed prospectively at three CF centers in the same visits on 154 test occasions across 62 children with CF (mean age: 22.7 months). Offline analysis using identical algorithms to the commercially available program provided outcomes of N2,original and N2,corrected for comparison with SF6 MBW. Mean functional residual capacity, FRCN2,corrected was 14.3% lower than FRCN2, original , and 1.0% different from FRCSF6 . Lung clearance index, LCIN2,corrected was 25.2% lower than LCIN2,original , and 7.3% higher than LCISF6 . Mean (SD) tidal volume decreased significantly during N2 MBWcorrected , compared to SF6 MBW (-13.1 ml [-30.7; 4.6], p < 0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCIN2,corrected and LCISF6 . The absolute differences in LCI increased significantly with higher LCISF6 (0.63/LCISF6 ) and (0.23/LCISF6 ), respectively, for N2,original and N2,corrected , but the relative differences were stable across disease severity for N2,corrected , but not for N2,original . Only minor residual differences between FRCN2,corrected and FRCSF6 remained to show that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N2 MBW did not affect differences. The corrected N2 MBW can now be used with confidence in young children with CF, although not interchangeably with SF6 .