Chloroquine, a well-known anti-malarial and anti-inflammatory agent, was studied with respect to its effect on the serum complement system. The drug exhibited significant in vitro anti-complementary activity only at a very high non-therapeutic dose of 48 mg/ml. Chloroquine-induced in vitro complement consumption was observed to take place even in the absence of Ca2+ and Mg2+ ions. The drug also haemolyses rabbit erythrocytes in the presence of Mg2+-EGTA and immunoelectrophoretic studies of fresh human serum and chloroquine incubation mixture against specific anti-C3 and anti-factor B antisera have demonstrated that it cleaves both C3 and factor B. In another experiment, chloroquine failed to exert inhibitory effects on complement utilisation by immune complexes. Studies of the serum complement profile of Plasmodium falciparum-infected malaria patients receiving chloroquine therapy indicated that, in contrast to the situation in vitro, the serum C3 level is invariably decreased. Marginal reductions in the levels of C4, factor B and properdin were also found in some of these patients, while administration of chloroquine to normal human individuals failed to produce any significant change in their serum complement profile. It is, therefore, probable that malarial parasites and not chloroquine are responsible for complement activation in patients suffering from malaria.