Abstract The anticoagulant activity of heparin is dependent on its affinity for antithrombin III (AT III) and on its molecular weight. In contrast, heparin fractions differing in these respects are equally effective inhibitors of the human complement system in vitro. In this study we designed and evaluated a model to investigate the effects of different heparin fractions on a complement dependent inflammation. Locally administered heparin, in a dose-dependent manner, inhibited the flare, itch and wheal responses induced by intradermal injection of heat-aggregated human IgG (HAGG). These reactions were also inhibited by the antihistamine mepyramine, favouring the view that HAGG activates complement and that the observed inflammatory response is mediated by anaphylatoxin liberation of histamine. Similar cutaneous reactions induced by trypsin, which can generate C3a and C5a by proteolysis of C3 and C5, the histamine liberator compound 48/80 or histamine were inhibited by mepyramine but not by heparin. Thus it is strongly suggested that heparin inhibits the HAGG induced reactions by modulating the early pre-C3 steps of complement activation. On a weight basis heparin fractions differing in AT III-affinity or in average molecular weight (5,000 and 16,000 D) were equally potent modulators of the HAGG-induced inflammation. We conclude that heparin can inhibit an apparently complement-dependent inflammation irrespective of its AT III-affinity or of its size, and suggest that a heparin with low anticoagulant activity could be of value as a modulator of inflammation and should be useful in investigating the consequences of complement inhibition in inflammation.