Objective: To determine the efficacy of a prophylactic regimen (prednisone, H1 blockade, and sympathomimetic amine therapy) in patients with idiopathic anaphylaxis. Design: Clinical trial before and after treatment. Setting: Referral-based allergy clinic at a major medical center. Patients: Fifty-three patients with a history compatible with idiopathic anaphylaxis for at least 6 months before presentation to the allergy service and with subsequent management by the service for at least 6 months. Interventions: Patients with frequent life-threatening symptoms were treated with a prophylactic regimen. Patients with infrequent episodes of idiopathic anaphylaxis were only treated acutely for each episode of anaphylaxis. Measurements and Main Results: The results favored prophylactic treatment with prednisone for patients who were classified as generalized-frequent in the clinical outcome measures of frequency (per patient per year) of episodes (mean before treatment, 7.31 ± 6.46; after treatment, 3.61 ± 4.73; P < 0.02) and emergency room visits (mean before treatment, 1.94 ± 3.42; after treatment, 0.21 ± 0.44; P < 0.005) and for patients classified as angioedema-frequent in the frequency of episodes (mean before treatment, 14.93 ± 15.89; after treatment, 2.58 ± 2.18; P < 0.003) and emergency room visits (mean before treatment, 0.76 ± 1.01; after treatment, 0.07 ± 0.11; P < 0.025). No statistically significant difference was found for patients classified as generalized-infrequent in the frequency of episodes (mean before treatment, 2.01 ± 1.30; after treatment, 1.36 ± 1.79) or of the emergency room visits (mean before treatment, 0.56 ± 0.71; after treatment, 0.32 ± 0.75) or for patients classified as angioedema-infrequent in the frequency of episodes (mean before treatment, 1.94 ± 1.55; after treatment, 2.03 ± 2.16) or of emergency room visits (mean before treatment, 0.27 ± 0.44; after treatment, 0.37 ± 0.59). Conclusions: Prophylactic treatment with prednisone and H1 antihistamines with or without sympathomimetic amines improves clinical outcome in patients who are classified as idiopathic anaphylaxis-angioedema frequent and idiopathic anaphylaxis-generalized frequent.