The polypeptides C3a and C5a are released as protein cleavage byproducts during activation of the complement system. These substances are able to release histamine from mast cells and this has generally been thought to be the link between complement activation and increased microvascular permeability in inflammatory reactions. Recent observations of inflammatory responses in the skin suggest that there is another link, which does not involve histamine. This is potentially of more general importance since antihistamines have limited effects on the majority of inflammatory reactions. One of the complement protein fragments, C5a (with or without carboxyl terminal arginine which is necessary for histamine release), is very potent in increasing vascular permeability. However, protein leakage leading to tissue oedema in skin is difficult to detect unless an arteriolar dilator is present. There is evidence that C5a and a vasodilator prostaglandin can be generated together extravascularly in response to a microbial stimulus. Unlike histamine, C5a does not act directly on venular endothelial cells, but triggers a very rapid interaction between circulating polymorphonuclear leukocytes and venular endothelial cells which, by an unknown mechanism, results in elevated venular permeability to plasma proteins.