I n a series of 40 patients treated with L-asparaginase for various neoplastic diseases, 6 patients had generalized anaphylactic reactions to L-asparaginase. Each of these reactors had antibodies detectable by passive hemagglutination, but precipitins were detectable in only one of this group of six patients. That patient had received two courses of the enzyme. 1 wk after the anaphylactic reaction, complement-fixing antibodies were present in all the patients that were studied. Specific reagin antibodies (IgE) were demonstrated in one patient by the release of histamine from his leukocytes after incubation in vitro with L-asparaginase.Binding of L-asparaginase to serum antibodies after incubation in vitro was detected by selective precipitation of the complexes with 30% ammonium sulfate or by ultracentrifugation. Total inactivation of the enzyme did not occur even at optimal proportions or at antibody excess.Passive hemagglutinating antibodies to L-asparaginase were present in all patients who had an allergic reaction at least 1 day before the reaction occurred, when that sample was available, and were absent in all patients who did not manifest clinical allergy. Titration of antibodies by passive hemagglutination may thus provide a means of predicting impending anaphylaxis in this system, particularly when coupled with a sudden decrease in circulating levels of L-asparaginase activity.