Twenty-three newborn infants with severe bilateral pulmonary disease and persistent pulmonary hypertension received mechanical ventilation to pH>7.55 and Paco2<25 torr. Response, as defined by attainment of a Pao2>100 torr, occurred in 87% of patients. Analysis of sequential arterial pH determinations revealed a linear increase in the number of infants responding as arterial pH increased. However, individual patients varied greatly in the optimal pH necessary to correct hypoxemia (range pH 7.50 to 7.75). Sixteen patients who had received mechanical hyperventilation were observed for 11.1±2.3 months. Virtually all had normal growth and development on follow-up physical and neurologic examinations, often despite profound or prolonged alkalosis and hypocarbia. In 11 infants at a corrected gestational age of 1 year, Bayley Scales of Infant Development revealed normal mental developmental indices (mean 106.2±15.4) and normal, but significantly lower, psychomotor developmental indices (93.2±11.7) (P<0.005). Although response and short-term outcome of neonatal hyperventilation appear favorable, this technique should be reserved for critically ill infants, because its long-term effects on the central nervous system are unknown.