The present study employed an animal model in an attempt to document effects on brain growth of long-term exposure to the ophylline in the presence or absence of malnutrition.One group of dams was randomly divided into half. One-half was fed a 20% protein diet and the other half a 6% protein diet. Similarly, a second group of dams was also randomly divided into two groups. These were pair-fed with rats of the first group, receiving diets comparable to those in group one but to which theophylline was added in amounts calculated to provide daily doses of 2 μg/100 g of body weight. Theophylline supplementation in the dams' 6% protein diet decreased the body weight of the pups consistently from d 3 to the end of the study at d 15 in comparison to the non-theophylline group. In contrast, the pres- ence of theophylline in the control diet increased the body weight of the pups at d 15 compared with that of the non-theophylline group. Brain weight was essentially identical in the normal controls and the normally nourished group given theophylline. No difference in brain weight was noted between the malnour- ished group and the malnourished group given theophylline.We found a significant reduction in DNA content per brain or per mg of brain weight in the normally nourished group given theophylline compared with non-theophylline group. DNA values per mg of brain weight from the controls that received theophylline were not different from either malnourished group. RNA, expressed as μg RNA per mg brain weight, was significantly reduced in the normally nourished group that received theophylline when compared with the normally nourished controls and the malnourished group that received theophylline.Total protein content per brain was significantly reduced in the malnourished group that received theophylline compared with non-theophylline group. A significant increase in the amount of protein in the malnourished groups as opposed to the normally nourished groups was measured (μg protein per mg brain).The brain cell size (protein:DNA) calculated by the standard method in the malnourished group supplemented with theophylline was smaller compared with that of the non-theophylline group, but cell size in the control group given theophylline was greater. It appears that theophylline supplementation in the maternal diet affects the cell size differently according to the nutritonal state of the offspring.Our data suggest that, in the animal model, the administration of theophylline in the presence of a compromised nutritional status may have effects not now apparent. We add our concern to that expressed by others that methylxanthine administration may have previously unsuspected effects on the developing brain.