1. The basic peptide substance P causes histamine release from peritoneal mast cells of the rat in vitro whereas the closely related neutral peptides eledoisin and physalaemin do not. 2. Infusion of substance P (7.4 nmol min-1), but not of eledoisin (8.4 nmol min-1) or physalaemin (7.9 nmol min-1), into the rat hindquarter preparation caused a more than 4-fold increase of the histamine content in the venous outflow. The outflow of 5-HT remained unchanged under infusion of all three peptides. 3. No histamine depletion in the skin of the rat hind paw was observed following antidromic stimulation of the saphenous nerve or cutaneous application of mustard oil. Infusion of substance P (7.4 nmol min-1) caused a 47% depletion of histamine in the paw skin although only a small proportion of the infused substance P seemed to enter the tissue from the blood vessels. 4. The results further substantiate the view that substance P upon release from peripheral nerve endings induces release of histamine from cutaneous mast cells, a mechanism which contributes to neurogenic vasodilatation and plasma extravasation.