To study the relative localization of alpha 1 and alpha 2-adrenoceptors in relation to the intima and the adventitia of canine saphenous vein, a comparison was made of the potency of alpha 1- and alpha 2-adrenoceptor agonists applied by intraluminal and extraluminal route of perfused segments of that vessel. Noradrenaline was the most potent of the agonists used and was approximately as potent by intraluminal as by extraluminal route. Cocaine (12 mumol/l) caused supersensitivity to noradrenaline which was of about the same magnitude (threefold) irrespective of the route of administration of noradrenaline. The selective alpha 1-agonist phenylephrine was about 10 times less potent than noradrenaline and was also equieffective by both routes. The selective alpha 2-agonist UK-14,304, at concentrations lower than 0.3 mumol/l, caused very small responses and only in 3 out of 14 experiments. In all cases it caused responses at concentrations higher than 0.3 mumol/l. Cocaine did not change the sensitivity to either phenylephrine or UK-14,304. Thus, it is concluded that the results obtained with cocaine agreed with expectations for a homogeneously innervated tissue. Furthermore, alpha 1-adrenoceptors seem to predominate and to be evenly distributed throughout the media. The lack of responses to the low concentrations of UK-14,304--those selectively acting on alpha 2-adrenoceptors--was ascribed to the very low efficacy of this agonist on the distal part of the canine saphenous vein and to the tone created by the perfusion pressure which might be high enough to mask this small response.