Immune hemolytic anemia (IHA) related to cephalosporins is rare and generally considered to be the result of a drug-adsorption mechanism. In previously reported cases, the hemolysis was usually extravascular and the causative antibodies were IgG, incapable of activating complement, and demonstrable by the direct or indirect antiglobulin test using red cells (RBCs) pretreated in vitro with cephalosporin. The authors report a patient in whom acute intravascular hemolysis developed while she was receiving cefotaxime (a cephalosporin as yet not reported to cause IHA). The patient's RBCs were coated only with complement fragments (C3d), even at the peak of the hemolytic episode. Her serum and eluates repeatedly yielded negative results when tested against normal or cephalosporin-coated RBCs. However, strong hemagglutination and C5b-9-mediated hemolysis were observed if the patient's serum was tested against RBCs in the presence of the drug, its ex vivo antigen and, to a lesser degree, cephalothin and ceftriaxon, but not in the presence of penicillin and other related cephalosporins. The positive reactions were not changed by preincubating the serum with different amounts of the drugs. All of these findings reflect the typical picture of drug-induced IHA by the so-called "immune complex" mechanism and not by the drug-adsorption mechanism. The authors conclude that cephalosporin can cause immune hemolysis in two ways: the drug-adsorption mechanism and, as described here, the "immune complex" mechanism.