Systemic anaphylactic reactions occur in a small percentage of patients receiving allergen immunotherapy. A 1 year study was performed in a large health maintenance organization to determine the incidence of systemic reactions (SR) to allergen immunotherapy. We measured the number of SR that occurred during a 12 months period. A SR data sheet was completed for each reaction, documenting the time of onset, symptoms, treatment, history of asthma or previous reaction, and concentration and type of extract. Twenty-seven thousand eight hundred six injection visits resulted in 143 SR (0.51%). Forty-five percent of the patients (pts) with SR had a history of prior SR, 50% had a history of asthma, and 36% developed reactions in season. Seventy-two percent of SR started within 30 minutes, although 8% appeared after 2 hours. Fifty-seven percent of SR occurred at concentrations of 1,000-10,000 PNU/cc, 25% at 10-100 PNU/cc, and 17% when both concentrations were given at the same visit. Eighty-three percent of SR were judged to be mild, nonlife threatening reactions, requiring no treatment or antihistamine therapy only. Seventeen percent were judged to be more severe, requiring treatment with epinephrine, with or without other agents. SR are a small but definite risk of immunotherapy. Most SR are mild, but some may be life threatening. The majority of reactions occur within 30 minutes, but significant reactions may occur after 2 hours. A large percentage of SR occurred in patients with a history of asthma, previous SR, or both.