Cocaine abusers frequently self-administer cocaine by different routes of administration. A controlled-dosing study was performed to assess the effect of different routes of administration on the excretion profile of cocaine and metabolites in urine. Single bioequivalent doses of cocaine were administered by the intravenous, intranasal, and smoked routes to six human subjects. Urine specimens were collected for 3 days after drug administration and were analyzed for cocaine, metabolites, and anhydroecgonine methyl ester, the thermal degradation product of cocaine, by gas chromatography-mass spectrometry. Cocaine was rapidly absorbed, metabolized, and excreted in urine. Peak cocaine concentrations were generally present in the first specimen collected; thereafter, concentrations declined quickly and were usually below the limit of detection (approximately 1 ng/ml) within 24 hours. The metabolite benzoylecgonine was present in the highest concentration and represented approximately 39%, 30%, and 16%, of the administered dose by the intravenous, intranasal, and smoked routes, respectively. Combined amounts of ecgonine methyl ester and six minor metabolites (norcocaine, benzoylnorecgonine, m-hydroxycocaine, p-hydroxycocaine, m-hydroxybenzoylecgonine, and p-hydroxybenzoylecgonine) accounted for approximately 18%, 15% and 8% of the administered dose by the intravenous, intranasal, and smoked routes, respectively. Anhydroecgonine methyl ester was present in trace amounts (0.02% dose) in specimens collected after smoked cocaine administration. Because many of these metabolites exhibit pharmacologic activity, their presence in urine may indicate that they play complex biologic roles in the overall activity of cocaine.