There are numerous drug-induced immediate hypersensitivity reactions (HSRs) that do not fit in Gell and Coombs’s Type I category of drug allergies, characterized by a pivotal role of allergen-specific IgE, Such non-IgE-mediated reactions, also referred to as “anaphylactoid, pseudoallergic or idiosyncratic”, are caused, among others, by radiocontrast agents, liposomal drugs and micellar solvent systems containing amphiphilic lipids or synthetic block-copolymers. A common feature of the latter agents is that they activate the complement (C) system, and that the reactions they cause can be explained with anaphylatoxin action. This chapter surveys the experimental and clinical evidence for the involvement of C activation in HSRs caused by agents in the above three categories. Further subjects include a proposal to update the classification of Type I allergy to according to the mechanism of mast cell (and basophil) activation, to direct and receptor-mediated reactions, with the latter category divided to IgE-mediated true allergy, C activation-related pseudoallegy (CARPA) and mixed IgE/C-triggered HSRs. The review also surveys the risk factors, laboratory prediction and pharmacological prevention of CARPA.