C5a has long been known to cause histamine release from isolated perfused guinea pig lung, isolated human basophils, rat and guinea pig mast cells, and guinea pig skin. The purpose of the present study was to compare the ability of guinea pig C5a to cause histamine release from lung fragments of dog, rabbit and rat with that released from guinea pig lung fragments. In addition, C5a-induced histamine release from the skin of the guinea pig, rabbit, and rat was investigated by examining antihistamine inhibition of C5a-induced vascular permeability changes. Guinea pig C5a caused a concentration-related release of histamine from guinea pig lung fragments with only minimal amounts of histamine being released from dog, rat, and rabbit lung fragments over the same concentration range. Guinea pig C5a also caused increased vascular permeability in guinea pig skin which was markedly inhibited by H1 antagonists. In rabbit skin, guinea pig C5a increased vascular permeability in the presence of PGE2 but the vascular leakage was unaffected by antihistamines. Rat skin was virtually unresponsive to C5a with or without PGE2. This data emphasize the differences between reactivity of species to C5a and the danger of extrapolating results obtained in one animal species to models employed with another species.