Introduction: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF₆MBW commonly viewed as the reference method. The use of N₂MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N₂signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF₆ and N₂MBW,corrected—such as tidal volume reduction during N₂ washout with pure O₂. Method: This was a longitudinal multicenter cohort study. SF₆MBW and N₂MBW 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 N_2,original and N_2,corrected for comparison with SF₆MBW. Results: Mean functional residual capacity, FRC_N2,corrected was 14.3% lower than FRC_{N2, original}, and 1.0% different from FRC_SF6. Lung clearance index, LCI_N2,corrected was 25.2% lower than LCI_N2,original, and 7.3% higher than LCI_SF6. Mean (SD) tidal volume decreased significantly during N₂MBW_corrected, compared to SF₆MBW (−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 LCI_N2,corrected and LCI_SF6. The absolute differences in LCI increased significantly with higher LCI_SF6 (0.63/LCI_SF6) and (0.23/LCI_SF6), respectively, for N_2,original and N_2,corrected, but the relative differences were stable across disease severity for N_2,corrected, but not for N_2,original. Conclusion: Only minor residual differences between FRC_N2,corrected and FRC_SF6 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 N₂MBW did not affect differences. The corrected N₂MBW can now be used with confidence in young children with CF, although not interchangeably with SF₆.