Several approaches have been undertaken in the study of possible immunologic cross-reactivity between cephalosporins and penicillins. Although the chemical structures of these compounds are similar in several respects, there are distinct differences in their degradation and transformation. Various degrees of cross-reactivity of antibodies produced in response to administration of these drugs have been demonstrated both with test systems that measure IgG and IgM antibodies and with those that measure IgE antibodies. The clinical significance of immune responses to cephalosporins is best understood in regard to immunohematologic abnormalities: positive direct antiglobulin (Coombs') tests occur in only approximately 3% of patients receiving cephalosporins; however, several cases of cephalosporin-induced immune hemolytic anemia have been reported. Clinical studies of the cephalosporins indicated that patients with a history of penicillin allergy have increased incidence of reactivity to cephalosporins, but it is impossible to determine to what extent this finding is due to immunologic cross-reactivity because penicillin-allergic patients have an increased incidence of hypersensitivity reactions to drugs immunologically unrelated to penicillins. In addition, there is evidence of specific immune response to cephalosporins that indicates independently acquired hypersensitivity rather than cross-reactivity in some patients.