The IgG antibody (Ab) response achieved with specific venom immunotherapy was explored in 32 patients with Hymenoptera hypersensitivity. Venom-specific IgG Ab was quantitated before and after 1 year of immunotherapy using two solid phase radioimmunoassay (SPRIA) methods. An agarose-based test using 125I-Staphylococcus aureus Protein A (SPRIA) was used to determine specific IgG for five Hymenoptera species: yellow jacket (YJ), honeybee (HB), yellow-faced hornet (YH), white-faced hornet (WFH), and Polistes (POL). A cellulose disk test using 125I-anti-IgG (IgG RAST) was available only for YJ and HB venoms. Acceptable agreement (90% concordance) was observed with IgG anti-HB levels measured in the two assays. For the YJ-IgG, however, 17/69 (25%) of sera positive in the SPRIA were negative in the IgG RAST, whereas the converse was not observed. This result suggests that the IgG RAST is insufficiently sensitive to detect YJ-IgG responses in all patients on maintenance level immunotherapy. Using the Protein A SPRIA, there was excellent agreement between the venom used for immunotherapy and the specificity of the IgG Ab response. In 31 patients treated with a total of 90 venom species, 90/90 venom IgG levels were increased or maintained at high pretreatment levels in response to immunotherapy. In the same patients venom IgG levels obtained for venom species not included in therapy were undetectable or declined in 55/60 cases; in 4 cases treatment with YJ venom stimulated a WFH and/or YH IgG response, the remaining case, YJ venom stimulated a small rise in POL IgG. These apparent discrepancies can be explained by variable cross-reactivity among vespid and POL venoms. Among 32 patients with a combined total of 87 positive venom skin tests, 1 year of specific immunotherapy resulted in greater than 5 micrograms/ml of venom-specific IgG in 61 instances. In 25 instances, the level of venom IgG was detectable but less than 5 micrograms/ml, and in 1 case venom IgG could not be detected. Based on recent analyses by Golden et al., some or all of these latter 26 cases may represent suboptimal therapy despite a standard immunotherapy regimen. We conclude that venom IgG measurements can provide a specific and quantitative assessment of the immunologic response to venom therapy, and that such assessment may be clinically useful in detecting instances of suboptimal immunotherapy.