Theophylline (T) tissue distribution was studied in 11 premature newborns treated with T for prematurity apnea, who had died from severe pathology. To investigate the pattern of distribution of T, in particular the role of the blood-brain barrier in this period of life, two animal species were employed (rat and guinea pig), differing widely in their postnatal development. T was administered to the animals acutely and chronically and the resulting data were compared to human findings. In human prematures no specific accumulation and a wide variety in tissue concentrations, as in tissue/blood ratios, were observed. In the rat, unlike the guinea pig, brain/blood ratios of T concentration declined as postnatal age rose, suggesting that development of the blood-brain barrier plays a major role.