The complement anaphylatoxin C3a from human or porcine serum contracts isolated peripheral airways from guinea pig in a manner which is independent of histamine release. In order to evaluate the role of arachidonic acid metabolites in the C3a response, dose-response curves for C3a-induced contractions of guinea pig lung strips were compared in the presence and absence of several inhibitors which block metabolism of arachidonic acid at relatively specific steps in the pathways. The inhibitor of leukotriene activity, FPL 55712, and the lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA), had no significant effect on the tissue response to C3a alone or in combination with antihistamine. The cyclooxygenase inhibitors, indomethacin and aspirin, however, both resulted in significant inhibition, causing a shift in the C3a dose-response curve to higher concentrations. When the antihistamine, pyrilamine, was included with either indomethacin or aspirin, the C3a response was inhibited further, although pyrilamine alone had no effect. Thus, C3a-induced contractions of isolated lung parenchyma are mediated primarily by cyclooxygenase metabolites of arachidonic acid. This result is in contrast to the finding that C5a anaphylatoxin mediates lung tissue contraction by release of lipoxygenase metabolites of arachidonic acid.