Plasma extravasation was induced in rats or guinea-pigs by intravenous injections of (1) substance P (SP), (2) the C-terminal SP-hexapeptide SP(6--11), (3) serotonin (5-HT), (4) histamine, (5) bradykinin, (6) capsaicin and (7) by antigen challenge. Plasma extravasation induced by SP, SP(6--11), by 5-HT and by capsaicin was, with few exceptions, observed in the same tissues. The effect of SP was not blocked by H1 and H2 histamine receptor antagonists. The effect of i.v. capsaicin was absent in capsaicin desensitized animals. Plasma extravasation upon i.v. SP, SP(6--11), 5-HT and capsaicin was seen in the skin and in all organs containing mucous membranes except the intestinal mucosa. Plasma extravasation by histamine, bradykinin, and antigen challenge of sensitized guinea-pig was, in addition, also observed in the stomach and intestine. Plasma extravasation and bronchoconstriction by antigen challenge with 20 micrograms/kg ovalbumin was completely blocked by combined H1 and H2 histamine receptor blockade. Both responses were reduced to about the half capsaicin desensitized guinea-pigs, although the reduction of the permeability response was statistically not significant in all organs. In conclusion, several substances including anaphylaxis induce protein leakage in many tissues with differing selective distribution patterns. Anaphylactic histamine release leads to protein leakage partly via activation of sensory neurons. SP is a likely mediator of neurogenic protein leakage in many organs.