Cocaine caused contractions and potentiation of motor responses to transmural stimulation of vas deferens of the rat but not of the guinea pig. Tachyphylaxis was not observed after repeated doses of cocaine to vasa deferentia from both normal and reserpine-treated rats. Pretreatment with reserpine reduced significantly (p < 0.05) the responses to cocaine but abolished completely the responses to tyramine. No catecholamines could be detected spectrophotofluorometrically in reserpine-treated preparations. Contractions following the application of cocaine to vasa deferentia from both normal and reserpine-treated rats were completely abolished by phenoxybenzamine, phentolamine, and tolazoline. Cocaine failed to protect alpha-adrenergic receptors against phenoxybenzamine blockade in reserpine-treated preparations; however, cocaine could still evoke contractions of reserpine-treated preparations protected with noradrenaline against phenoxybenzamine blockade. The evidence presented indicates that cocaine acts as a mixed sympathomimetic on the rat vas deferens preparation. The possibility that cocaine is an indirect-acting sympathomimetic amine could not be ruled out in the present study.