Haemoglobin (Hb) desaturation could increase the risk of stroke in sickle cell anaemia (SS) by perturbing endothelial function and limiting oxygen delivery to the brain. We performed a nested case-control study of the Dallas Newborn Cohort to determine whether daytime steady-state Hb desaturation was associated with overt stroke in children with SS. Cases had SS and overt ischaemic strokes. Controls had comparable genotypes but no overt stroke. Cases had lower prestroke steady-state pulse oximetry values (SpO(2)) than controls, and cases' SpO(2) fell even lower as the time to impending stroke decreased. The odds ratio for stroke was 1.32 for each 1% decrease in SpO(2). In conclusion, steady-state Hb desaturation is a risk factor for overt ischaemic stroke in children with SS. Decline in SpO(2) over time further increases this risk. Hb desaturation is easily measured, potentially modifiable, and could be used to identify children with SS at increased risk of stroke.