The effect of the adenosine analogue L-N-phenyl-isopropyl-adenosine (L-PIA) and theophylline on the respiration of rabbit pups was studied. L-PIA (5 mumol/kg) administered intraperitoneally caused a marked respiratory depression in urethane-anaesthetized decerebrate pups and unanaesthetized intact animals during natural sleep. The effect could often be reversed with theophylline. When L-PIA was given after theophylline (20 mg/kg), the effect of L-PIA was considerably lower. L-PIA also caused respiratory depression when administered onto the exposed surface of the fourth ventricle. The effect of the adenosine analogue was more pronounced in younger than in older animals. We conclude that adenosine strongly inhibits respiration and that effect is antagonized by theophylline. The hypothesis is put forward that the therapeutic effect of theophylline on neonatal apnea might be exerted via adenosine antagonism rather than via inhibition of phosphodiesterase. Apnea in infants is often triggered by hypoxemia. It is possible that adenosine, which is released during hypoxia, mediates this effect.