The effect of aminophylline on cerebral blood volume and oxidative metabolism in newborn infants was investigated with near infrared spectroscopy (NIRS). Thirteen mechanically ventilated premature infants who received aminophylline to facilitate weaning from the respirator were selected. Gestational age ranged between 26 and 34 weeks, postnatal age between 1 and 7 days and birth weight between 760 and 2300 g. A bolus of 6 mg aminophylline/kg body weight was infused within 2 min. NIRS was performed continuously across the head to monitor changes in cerebral blood volume and cytochrome c oxidase. Heart rate, transcutaneous carbon dioxide tension (tcpCO2) and arterial haemoglobin oxygen saturation (SO2) were recorded simultaneously. The infusion of aminophylline was associated with an increase in heart rate (median 12, interquartile range 5-20 beats per min, P = 0.0004) and a drop in tcpCO2 (median -0.4, interquartile range -0.1 to -0.5 kPa, P = 0.015). Oxygen saturation remained stable (+/- 3%). A decrease in cerebral blood volume was measured with NIRS in 9/13 patients (median -0.15 ml/100g brain tissue, interquartile range +0.08 to -0.28, P = 0.10). Oxidized cytochrome c oxidase decreased in 11/13 patients (median -0.27 mumol/l, interquartile range -0.19 to -0.44, P = 0.01). Our findings demonstrate an immediate step-response of heart rate and tcpCO2 to aminophylline in premature infants. The simultaneous reduction of cytochrome c oxidase in the brain cannot be explained as a consequence of changes in tcpCO2 or changes in cerebral blood volume. We therefore speculate that aminophylline interferes directly with cerebral metabolism.