The purpose of this study was to characterize the mode of action of the venom from Portuguese man-of-war (Physalia physalis) on the skeletal muscle vascular bed of dogs anesthetized with sodium pentobarbital (35 mg/kg). Venous outflow and the blood pressure difference across the hind-limb vascular bed were used to calculate changes in resistance due to close arterial injections of the venom (0.001-1 microgram/kg). The venom consistently produced dilations that were blocked by sodium meclofenamate (5 mg/kg). Atropine (1 mg/kg), propranolol, phentolamine, cimetidine (each 2 mg/kg) or tripelennamine (2.5 mg/kg) had no significant blocking effect. The venom also produced transient dilations on vascular beds predilated with histamine or prostaglandin E1, or preconstricted with norepinephrine (each 0.01 microgram/kg) or by sympathetic stimulation (12 V, 20 Hz). These data suggest that Physalia venom dilates skeletal muscle vasculature primarily by stimulation of endogenous prostaglandin synthesis.