We have developed a method to evaluate the diffusion of ammonia across the blood-brain barrier (BBB) in normal humans, based on measures of CBF and the regional cerebral metabolic rate for ammonia, obtained by positron emission tomography. The extraction fraction for ammonia passing through the cerebral capillary bed was a reciprocal function of CBF. The product of the BBB surface area and ammonia permeability, calculated from the Renkin-Crone model, was 0.32 +/- 0.19 cm3 g-1 min-1 (+/- SD) in gray matter and 0.24 +/- 0.16 cm3 g-1 min-1 in white matter. From literature values of the expected capillary surface area ratio, a gray-to-white matter ammonia permeability ratio of 0.37:1.0 was calculated. We speculate that astrocytes may mediate this unexpected difference in permeability, and that the permeability of the BBB to ammonia may be important in the pathogenesis of hyperammonemic brain dysfunction.