Administration of bovine tetanus antitoxin to a patient who was sensitive to horse serum was followed by serum disease. Immunological studies revealed a preexisting hemagglutinating antibody titer of 2,000 against horse serum, but none to bovine serum. After the onset of symptoms, both titers rose. The reaction against bovine serum reached a titer of 100,000. A transitory skin-sensitizing antibody against bovine serum was also produced. An alpha globulin component of bovine serum was found to be the precipitating antigen. Thus, this patient probably reacted to a serum fraction other than the active antitoxin. The results suggest an antigenic cross relationship between horse and beef sera, limiting the usefulness of bovine antitoxin. Greater use of toxoid could help eliminate the problem of serum reactions. Certainly, horse-serum sensitivity should make active immunization mandatory.