We studied the transport of 14C-caffeine across the blood-brain barrier (BBB) by measuring brain 14C:3H ratios five seconds after rats received the caffeine, with 3H2O, by intracarotid injection. Caffeine was found to enter the brain by both simple diffusion and saturable, carrier-mediated transport. This latter observation suggested to us that caffeine's transport might involve macromolecules that are structurally similar to caffeine. Hence, we examined caffeine's ability to inhibit the BBB transports of 14C-adenosine and 14C-adenine. Caffeine caused a dose-dependent inhibition of 14C-adenine transport but no clear change in that of 14C-adenosine. At very high blood levels (Ki = 9.8 mM), caffeine may restrict the availability of circulating purines to the brain. This effect may be important neonatally, when carrier-mediated adenine transport apparently is maximal.