In order to test the practicability and safety of whole-body cooling in term neonates with moderate-to-severe hypoxic-ischaemic encephalopathy (HIE) and to report outcomes, a prospective pilot study was carried out in 25 term infants (median postmenstrual age 38 weeks, range 36 to 41 weeks; 20 males, five females). Whole-body cooling, to a target core temperature of 33 to 34 degrees C, started within 6 hours of birth and was maintained for 72 hours. Of the 25 newborn infants (19 Sarnat II and six Sarnat III, 18 outborn), 18 survived, including 13 (72%) with normal cerebral signal by MRI. Temperature instability occurred during cooling in 15 infants, but neither severe haemodynamic instability nor renal failure was seen. Thrombocytopenia developed in 12 infants, including seven with biological disseminated intravascular coagulation. One patient had hypoxaemia with right-to-left shunting through the ductus arteriosus, and seven had limited meningeal or subdural bleeding. Whole-body cooling is feasible in term neonates, with no life-threatening adverse events. Improvements are needed to obtain stable hypothermia for 72 hours.