Administration of Carbrital® (a combination of carbromal and pentobarbital sodium) was accompanied by the development of a positive direct antihuman globulin reaction in three of 143 patients. The finding appeared related to the development of antibodies to carbromal, which were able to agglutinate and to sensitize to antihuman globulin red cells coated with carbromal, but not red cells coated with pentobarbital sodium, penicillin or chlorpromazine. Studies of inhibition by 2-mercaptoethanol and behavior in the ultracentrifuge of the patients' sera and of eluates from coated erythrocytes demonstrated antibodies of the 7S and 19S type, the former responsible for the sensilization of the drug-coated red cells and the latter responsible for the direct agglutination of normal cells coated with carbromal by the patients' sera. Mechanism of activity of the antibody seemed similar to that observed with antipenicillin antibodies, the antibodies being directed against the drug and the positivity of the Coombs' test being related to the reaction of the antibody with the drug on the surface of the red cell. As opposed to the findings with penicillin sensitivity, however, no overt nor occult hemolytic anemia was noted in the three patients studied. Relatively low titer of antibodies might account for this discrepancy.