Normal guinea pigs that have been intradermally injected with C1s exhibit increased vascular permeability at the injection site. Guinea pigs that are genetically deficient in complement component C2 do not exhibit increased vascular permeability when given a similar injection. The C2-deficient guinea pigs respond normally to injections of bradykinin and kallikrein, suggesting that these animals can respond to kinins and have a normal kininogen pathway. When the C2-deficient guinea pigs are given guinea pig C2 before C1s injection, increased vascular permeability is observed. These results demonstrate a definite requirement for complement component C2 in the generation of C1s-induced vascular permeability.