Azidothymidine (AZT) crosses the blood-brain barrier (BBB) of 6-8 week old Sprague-Dawley male white rats (Oldendorf technique, ipsilateral cerebral hemisphere) with a brain-uptake index (BUI) of 5.4 +/- 0.8 (mean +/- S.D., n = 13, range 4.4-6-6) using 14C-antipyrine as the diffusible standard. Pretreatment of the animals with the higher doses of insulin (0.6 or 1.0, but not 0.1, 0.2, or 0.3 units per rat, 3 or 10 min. before decapitation) resulted in higher values for the BUI of AZT in most individual animals. In the group of rats treated with 1.0 unit of insulin 10 min. before decapitation, a statistically significant increase in the BUI was observed. Some possible clinical applications of this pharmacologic strategy are discussed.