Studies with [14C]methylphenidate-HCl were carried out in rats administered the drug intravenously or intraperitoneally. Levels of total radioactivity and parent drug were measured in plasma, brain, and certain brain regions up to 6 hr after dosing. The intravenous route of administration was characterized by rapid entry into brain; during the first half hour, brain levels were 3- to 6-fold higher than those obtained by the intraperitoneal route. At later time periods, brain and plasma concentration for both routes were comparable, and the decline of drug concentrations in brain paralleled that in plasma. No significant variance was found in regional distribution of drug in brain. Whereas the major fraction of circulating drug consisted of metabolites, predominantly unchanged drug was found in brain. After intravenous injection of [14C]ritalinic acid (the major metabolite of methylphenidate), no substantial concentrations were found in brain.