The pharmacological interaction between equipotent doses of ethanol (1.35 g/kg) and delta-9-tetrahydrocannabinol (THC, 17 mg/kg) was evaluated in mice using rotarod performance as a measure of drug action. Tolerance ot the effects of ethanol and THC as well as a symmetrical cross-tolerance between these two drugs was demonstrated. Ethanol elimination was not altered by previous treatment with either ethnaol or THC as determined by measuring blood ethanol concentrations with an enzymatic assay. THC metabolite ratios in blood, brain and liver tissues determined after a dose of 3H-THC demonstrated that THC treatment had no effect upon THC metabolism or disposition. Ethanol treatment altered the distribution of THC and also altered hepatic THC metabolism as evidence by the occurrence of increased proportions of polar THC metabolites. No treatment regimens produced lower whole brain levels of subsequent ethanol or THC suggesting that tolerance to ethanol or THC and cross-tolerance between these two drugs does not develop due to lower brain concentrations. A vehicle effect was shown when treatment with a mixture of propylene glycol and Tween-80 altered the metabolic and behavioral effects of subsequently administered THC.