Skin testing and immunotherapy with allergens can induce systemic allergic reactions. In order to identify factors associated with systemic allergic reactions, a prospective study was conducted from 1976-1989 with more than 10,000 patients being tested and a total of 513,368 injections being recorded. Our study showed that the probability of inducing systemic allergic reactions by skin testing was less than 0.02% and the probability of systemic allergic reactions caused by immunotherapy was 2.9%. The female to male ratio was 3 to 2. The highest incidence of systemic allergic reactions was in patients between the ages of 16 to 39 years of age. The majority of systemic allergic reactions occurred when patients were on increasing doses rather than maintenance doses. More than 95% of systemic allergic reactions were associated with pollens and most of them happened between the concentration of 100 and 1000 PNU/mL. There was no increased incidence during grass or ragweed pollination seasons in those patients who received grass or ragweed injections during the respective seasons. Only 50% of systemic allergic reactions developed within 30 minutes after injections. The three most important factors determining the incidence of systemic allergic reactions are the type of allergens, the "rate" of increase of allergen concentrations, and sensitivity of the patients to allergens. The prick test at initial allergy assessment can be used to "rule out," with a high degree of certainty, the likelihood of systemic allergic reactions. The prick test is easy to perform and it is cost-effective. Prick tests and RAST together are helpful in identifying the patients and the allergens at higher risk of systemic allergic reactions.