Abstract: Zinc-65 transport into different regions of rat brain has been measured during short vascular perfusion of one cerebral hemisphere with an oxygenated HEPES-containing physiological saline at pH 7.40. The [Zn2+] was buffered with either bovine serum albumin or histidine. In each case uptake was linear with time up to 90 s. 65Zn flux into brain in the presence of albumin followed Michaelis-Menten kinetics and for parietal cortex had a Km of 16 nM and a Vmax of 44 nmol/kg/min. Increasing concentrations of l-histidine enhanced 65Zn flux into brain at [Zn2+] values between 1 and 1,000 nM. The combined effect of [histidine] and [Zn2+] was best accounted for by a function of [ZnHis+], i.e., flux = 64.4 · [ZnHis+]/(390 + [ZnHis+]) + 0.00378 · [ZnHis+], with concentrations being nanomolar. d-Histidine had an influence similar to that of l-histidine. 65Zn flux in the presence of 100 µMl-histidine was not affected by either 500 µMl-arginine or 500 µMl-phenylalanine. The results indicate specific transport of Zn2+ across the plasma membranes of brain endothelium. The enhancement due to histidine has been attributed to diffusion of ZnHis+ across unstirred layers “ferrying” zinc to and from transport sites.