Bilateral electrolytic lesions were placed in the anterior basal hypothalamus of male Hartley strain guinea pigs. The animals with anterior hypothalamic lesions and a group of sham operated controls were sensitized 5 to 10 days postoperatively with ovalbumin in modified Freund's adjuvant. At 18 to 22 days following sensitization, both groups were randomly divided into 3 subgroups, and challenged by intrajugular injections of 3 different antigen doses. Anaphylactic death and the severity of anaphylaxis in the survivors were recorded. Antibody titers were determined prior to challenge with use of the passive cutaneous anaphylaxis technique. Serial sections of each brain were made for lesion localization. Significant protection against anaphylaxis was found in guinea pigs with symmetrical lesions in the anterior hypothalamus. No significant differences in antibody titers were observed between the lesion and sham operated groups. There were no significant differences in the response of isolated muscle strips from anterior lesioned and sham operated guinea pigs to exogenous histamine. Anterior hypothalamic lesions of size and location comparable with those that provided protection against lethal anaphylaxis did not modify the anaphylactic response of isolated ileum from actively sensitized animals or following passive sensitization in vitro.