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Commercial airplanes fly with an equivalent cabin fraction of inspired oxygen of 0.15, leading to reduced oxygen saturation (SpO2) in passengers. How this affects children with complex congenital heart disease (CHD) is unknown. We conducted Hypoxic Challenge Testing (HCT) to assess need for inflight supplemental oxygen.Children aged <16 years had a standard HCT. They were grouped as (A) normal versus abnormal baseline SpO2 (≥95% vs <95%) and (B) absence versus presence of an actual/potential right-to-left (R–L) shunt. We measured SpO2, heart rate, QT interval corrected for heart rate and partial pressure of carbon dioxide measured transcutaneously (PtcCO2). A test failed when children with (1) normal baseline SpO2 desaturated to 85%, (2) baseline SpO285%–94% desaturated by 15% of baseline; and (3) baseline SpO275%–84% desaturated to 70%.There were 68 children, mean age 3.3 years (range 10 weeks–14.5 years). Children with normal (n=36) baseline SpO2 desaturated from median 99% to 91%, P<0.0001, and 3/36 (8%) failed the test. Those with abnormal baseline SpO2 (n=32) desaturated from median 84% to 76%, P<0.0001, and 5/32 (16%) failed (no significant difference between groups). Children with no R–L shunt (n=25) desaturated from median 99% to 93%, P<0.0001, but 0/25 failed. Those with an actual/potential R–L shunt (n=43) desaturated from median 87% to 78%, P<0.0001, and 8/43 (19%) failed (difference between groups P<0.02). PtcCO2, heart rate and QT interval corrected for heart rate were unaffected by the hypoxic state.This is the first evidence to help guide which children with CHD need a preflight HCT. We suggest all children with an actual or potential R–L shunt should be tested.