There is growing awareness that numerous drug-induced immediate hypersensitivity reactions (HSRs) do not fit in Gell and Coombs' Type I category of drug allergies, characterized by the pivotal pathogenic role of allergen-specific IgE. Such non-IgE-mediated "pseudoallergic" reactions are primarily caused by (1) certain liposomal formulations of intravenous drugs and imaging agents, (2) infusion liquids containing micelle-forming amphiphilic lipids or synthetic block-copolymer emulsifiers, and (3) iodinated radiocontrast media with limited solubility in water. Common features of the latter "pseudoallergens" include the capacity to activate the complement (C) system; also, the symptoms they cause are often typical manifestations of excessive anaphylatoxin generation in blood. Hence, these reactions have been called "C activation-related pseudoallergy" (CARPA). The present review surveys the experimental and clinical evidence for the involvement of C activation in HSRs caused by pseudoallergens in the above, three categories. To fit CARPA within the classical scheme of HSRs, a subdivision of Type I allergy is proposed on the basis of the mechanism of mast cell (and basophil) activation. The new scheme distinguishes direct and receptor-mediated HSRs, with the latter category subdivided to true IgE-mediated allergy; anaphylatoxin-mediated CARPA; and IgE plus anaphylatoxin double-triggered reactions. Further issues addressed in the review include animal models, risk factors, laboratory predictive tests, and pharmacological prevention of CARPA.