Two comparable groups of asthmatics each with 10 patients were treated during 2 years at scheduled intervals with either natural or synthetic ACTH up to a total dose of 2000-95-- IU. All patients had previously been given the natural but never the synthetic hormone. Intradermal tests with natural and synthetic ACTH were performed before treatment and after 1, 12 and 24 months. Serum samples were also taken on these occasions and analysed for antibodies against ACTH, vasopressin and porcine gamma-globulin. No sign of clinical allergy to ACTH was noted in any of the patients during the 2-year period. The incidence of intradermal reactions against natural ACTH was high at the onset of treatment but was not increased by treatment with either synthetic or natural ACTH, while the reactivity rate against synthetic ACTH was increased after both types of treatment. The incidence of IgE reactions against synthetic ACTH at the 20 U/ml level was significantly increased after 12 months' treatment with either natural or synthetic hormone. A high incidence of low-titered agglutinating antibodies against natural or synthetic ACTH was demonstrated before treatment in both the groups, but no significant change in incidence or mean titre against natural or synthetic ACTH or porcine gamma-globulin was noted during treatment with the natural or the synthetic preparation. A few patients, however, did display an increased agglutinating titre against ACTH after 12 months' treatment. Rather unexpectedly, most sera reacting with ACTH were found to react also with vasopressin and a significant increase of the incidence of these reactions and of the titres occurred during the treatment with synthetic as well as with natural ACTH. Two cases have been examined in detail, one because of a fulminant shock after synthetic ACTH and the other because of very high antibody titres without clinical symptoms of ACTH allergy.