Positive direct antiglobulin tests (DATs) associated with cephalosporin therapy have been reported, but rarely were associated with immune hemolytic anemia (IHA). In 1989, we described the first case of IHA associated with cefotetan (Cefotantrade mark) causing hemolysis by the drug-adsorption mechanism. We now report the full details of ow investigation. The patient was a 23-year-old female with a 2 1/2 year history of chronic ulcerative colitis. After 4 days of therapy with cefotetan (2 g/day), her hematocrit (Hct) decreased from 34.351 to 23.3%. The reticulocyte count was 6.9%. The DAT was 2+ (IgG only), and the serum and an eluate were nonreactive with a panel of standard reagent red blood cells (RBCs). Cefotetan therapy continued and the patient was transfused with two units of RBCs. On day 6 of therapy, the patient experienced an anaphylactoid reaction attributed to sensitivity to cefotetan. Cefotetan therapy was discontinued, the patient was treated with corticosteroids and epinephrine, and she was transfused with an additional unit of RBCs. Her Hct rose to 34.1% prior to her discharge on day 11. Further investigation revealed that the patient's serum and an eluate contained an antibody that reacted with cefotetan- and cephalothin-coated RBCs by the indirect antiglobulin test. In a monocyte monolayer assay, monocytes readily phagocytized cefotetan- and cephalothin-coated reagent RBCs but not uncoated reagent RBCs. The patient's serum did not react by the so-called immune-complex mechanism when cefotetan or cephalothin was added to the patient's serum + complement + RBCs.