Although true allergic reactions due to systemic corticosteroid therapy are not frequent, they should be kept in mind since allergic reactions to this kind of therapy are possible. We report two cases of specific adverse reactions resulting from systemic corticosteroid therapy which were diagnosed by provocation tests. The corticosteroids involved in each case were paramethasone and betamethasone, and methyl-prednisolone in both of them. Additives and other corticosteroids were studied by skin tests and challenges, with negative results. The structures of paramethasone and betamethasone are similar, with a 16 carbon methyl group in both, and with a fluoride in the alpha position of the 6 carbon in paramethasone, and a fluoride in the beta position of the 9 carbon and a 6 carbon methyl group in betamethasone. Methyl-prednisolone differs from that of other corticosteroids in its 6 carbon methyl group. We report two cases of specific adverse reactions caused by corticosteroids. Positive challenge tests showed a possible immunologic hypersensitivity mechanism in both cases. The patients' reactions demonstrated cross-reactivity between methyl-prednisolone and the corticosteroids having a 16 carbon methyl group, and fluoride or methyl radicals on the 6 carbon.