When purified human C′1 esterase is injected intradermally in man, increased vascular permeability results. This effect is not blocked by soybean trypsin inhibitor and is not abolished by pretreatment with the antihistamine, pyribenzamine, or by compound 48/80. Thus, the effect is not due to the release of endogenous histamine. The decreased permeability response of individuals with a specific hereditary deficiency of C′2 is evidence for the complement-dependent nature of this reaction. The apparently normal response to intradermal C′1 esterase developed by individuals with an acquired specific deficiency of C′3 suggests that the vasoactive substance may be derived from one of the early reacting complement components. Characteristic attacks of angioedema have been provoked by the intradermal injection of human C′1 esterase in two individuals with hereditary angioneurotic edema. Patients with hereditary angioneurotic edema are unresponsive to intradermal injections of C′1 esterase immediately after attacks.