In rats with experimental chronic renal insufficiency (90% nephrectomy) the histidine content in brain was increased (+ 35%) in spite of normal plasma values and decreased concentrations in the striated muscle (-23%). The finding of a raised histidine level in the brain seems to be a uremia specific disorder, probably cuased by a local disturbance in histidine metabolism. In addition an increase of the histidine decarboxylation product histamine could be observed in the brain of rats with chronic renal insufficiency, as compared to pair-fed controls. This increase was directly related to the severity of azotemia. In the pathogenesis of the histamine alteration the increased histidine content in the brain of uremic rats must be considered, since the specific histidine decarboxylase is not saturated by the normal endogenous level of the amino acid precursor. Probably the increased histamine contributes to the raised cerebral cyclic AMP in the brain of uremic rats.