The aim of the present study was to provide evidence for an interaction of dihydroergotamine (DHE) and etilefrine (Et) with regard to their constrictor effect on human leg veins both in vitro and in situ. In isolated strips of the femoral vein, DHE exerted a concentration-dependent sustained contraction which also continued after washing out the preparation. Et induced a reversible contraction of the strip at considerably higher concentrations as compared to DHE and noradrenaline. When DHE (0.01 mumol/l) and Et (6 mumol/l) were simultaneously applied, there was only an additive venoconstrictor effect. The influence of DHE and Et on the compliance of dorsal foot veins was studied in 14 male volunteers by means of a variable differential transformer. In the short-term experiment, an oral dose of 10 mg DHE was ineffective, whereas after the subcutaneous injection of 1 mg DHE a significant venoconstrictor effect was observed. Et, orally given in a dose of 10 mg, was also ineffective, while 20 mg Et caused a short-lasting effect which could not be augmented by the concurrent intake of 10 mg DHE. When 10 mg Et were administered 30 or 60 min after a single oral dose of 10 mg DHE, a distinct venoconstrictor effect occurred. These findings suggest that no pharmacodynamic synergism of the two drugs can be expected when DHE and Et directly act on the veins. The augmentation of the venoconstrictor in situ effect of Et after pretreating the volunteers with DHE could result from an amelioration of the oral bioavailability of Et by DHE, i.e., from a pharmacokinetic interaction of the two drugs.