1. The relationship between the chemical structure and the direct vasoactivity of different prostaglandins administered intra-arterially was studied in the dog hindlimb preparation.2. All of the prostaglandins studied, except PGF(1alpha) and PGF(2alpha), caused a dose related decrease in the femoral arterial perfusion pressure in dogs in which the femoral arterial blood flow was kept constant, indicating the direct vasodilator action of these prostaglandins.3. Among the prostaglandins studied, PGE(1) is the most potent vasodilator. Comparing the chemical structure and vasodilator action of PGE(1) with those of different prostaglandins, the following conclusions can be made:4. The formation of the Delta(5) double bond in PGE(1) causes no change in its vasodilator activity, whereas the saturation of the Delta(13) double bond of PGE(1) slightly reduces its activity.5. The alterations in the orientation and length of the carboxyl and alkyl side chains reduce markedly the vasodilator action of PGE- and PGA-compounds.6. The presence of a carbonyl group at C9 is the most important requirement for the potent vasodilator action of PGE(1). On the other hand, the presence and S-configuration of a hydroxyl group at C15 are essential for the intrinsic action at the receptor sites in the vascular smooth muscle, but may not be responsible for the vasodilator action.7. The esterification of PGE(1) or PGE(2) and a triple bond formation and the replacement of C7 with oxygen in prostaglandin appear to reduce or abolish their vasodilator action.