Nitric oxide inhalation can benefit newborn babies with right-to-left extrapulmonary shunt (EPS). Using doppler ultrasound, we compared the effects of nitric oxide on systemic oxygenation and mean pulmonary-blood-flow velocity (MPBFV) in severely hypoxic babies with or without EPS. With a median (interquartile range) dose of 20 (32) parts per million, oxygenation index decreased significantly in both groups (EPS, 49  vs 11 ; non-EPS, 40  vs 20 ). The decrease was significantly greater in the EPS group. MPBFV increased significantly in the EPS group (18  vs 29  m/s) only. Nitric oxide may improve systemic oxygenation in neonates with severe hypoxaemia secondary to EPS by increasing pulmonary blood flow, and in those without EPS by improving ventilation-perfusion matching.