The subtype selectivity of the alpha 1-adrenoceptor antagonist, tamsulosin, was tested using hepatocytes and liver membranes from guinea pigs and rabbits (expressing alpha 1-adrenoceptors with alpha 1A pharmacology) and rats (alpha 1B-adrenoceptors). Tamsulosin blocked the alpha 1-adrenergic activation of phosphorylase with higher affinity in hepatocytes from guinea pigs and rabbits than in those from rats. [3H]Tamsulosin binding to liver membranes was rapid, reversible and saturable. The Kd values obtained also indicated higher affinity for alpha 1A-adrenoceptors (70 and 140 pM, for liver membranes obtained from guinea pigs and rabbits, respectively) than for those of the alpha 1B-subtype (510 pM). Chloroethylclonidine potently and completely inactivated [3H]tamsulosin binding sites in membranes from rabbit and rat livers, but not those in guinea pig liver membranes. Binding competition and inactivation experiments were performed to further characterize the receptor subtypes present in the livers of these animals. In summary, tamsulosin is a very potent alpha 1-adrenoceptor antagonist that has higher affinity for alpha 1A-adrenoceptors than for those of the alpha 1B-subtype.