After a decade spent establishing the safety, efficacy, and optimal techniques for venom immunotherapy, we have begun a series of studies to determine how long venom immunotherapy must be continued. In retrospective surveys, patients who had stopped venom immunotherapy after 1 to 2 years had a substantial risk (25%) of systemic sting reactions, but this was less than 50% of the risk in untreated patients. In this first prospective study, 30 patients elected to stop venom immunotherapy after at least 5 years of therapy. Skin test sensitivity had decreased significantly during therapy in 18/30 patients but remained clearly positive in 23/30 (seven patients became equivocal or negative). Serum venom-specific IgE antibodies were at the lower limit of detection (1 ng/ml) in 11/30 patients. After stopping treatment, the mean serum venom-specific IgG antibody level declined from 5.5 +/- 0.6 micrograms/ml to 2.4 +/- 0.3 micrograms/ml by 9 months, which is the same as the mean venom IgG in untreated patients. After 12 months without therapy, live sting challenge caused no systemic reaction in 29 patients. The mean venom IgG level 1 month after the sting had risen significantly to 4.1 +/- 0.5 micrograms/ml, but there was no significant increase of venom IgE. These results suggest that prolonged venom immunotherapy leads to isotype-specific suppression of the venom IgE antibody response and may provide persistent clinical protection by mechanisms other than IgG blocking antibodies. The observations are to be interpreted very cautiously. Further investigations are needed to extend these observations in additional patients and for longer periods of time, and to examine possible mechanisms for this apparent loss of clinical reactivity.