Rats were maintained on liquid diets containing ethanol (6.8% v/v) or sucrose (controls) for periods of 2 and 6 wk to determine whether excised aortic or venous (portal vein) smooth muscle would exhibit any change in tone or reactivity when exposed to vasoactive agonists or to added ethanol (ETOH) in vitro. The results indicate that portal veins (PV) from the 2‐wk ETOH group show marked attenuation of (A) spontaneous tone, (B) angiotensin and K+‐induced contractions, and (C) Ca2+‐induced contractions. In contrast, PV from rats on ETOH for 6 wk only show depression of tone and Ca2+‐induced responses when compared to sucrose‐fed controls. Exposure of the PV to ethanol in vitro inhibits spontaneous tone of control sucrose‐fed animals but exerts little action on PV obtained from ETOH‐maintained rats. Although the addition of a high bathing concentration of ETOH (430 m/W) can evoke potent contractions in normal aorta, it fails to exert such action in most aortas obtained from rats maintained on ETOH. In vitro ETOH also dose‐dependently inhibited all drug‐induced contractions of blood vessels from control rats, but exerted little inhibition on PV and aortas obtained from ETOH‐maintained rats. These data indicate (1) chronic ETOH ingestion can directly influence vasomotor tone, reactivity of vascular muscle, and permeability of vascular membranes to Ca2+; (2) chronic ETOH treatment can induce a progressive “tolerance” in vascular tissue; and (3) the development of tolerance in vascular smooth muscle to ETOH may aid in explaining why long‐term alcoholic animals and man do not dev