Background: Venom immunotherapy (VIT) induces immune tolerance to hymenoptera venom antigens in allergic patients and is therefore a helpful model for studying modulation of allergic immune response. The objectives were to assess the early effects of ultra-rush VIT on T lymphocyte activation and regulatory profile induction, in all subjects combined and according to the four severity grades of the Mueller classification. Materials and methods: Blood samples from 30 vespid-allergic patients were taken before and after the first day of treatment, and before day 15 and day 45 booster injections. IFN-gamma and IL-4 levels were assayed by ELISA, in whole-blood supernatants. IFN-gamma and IL-13-producing T cells, but also natural CD4+CD25+high regulatory T cells and acquired regulatory T cell proportions were assessed by flow cytometry. Results were analysed in the whole population and compared between patients with I-II or III-IV allergic reactions. Results: During VIT, IFN-gamma increased in whole blood when IL-4 decreased. Among T cells, the percentage of CD3+IFN-gamma+ cells increased while IL-13-producing T cells decreased. Proportions of CD4+CD25+high cells and IL-10-producing T cells increased with VIT. In I-II subjects, IFN-gamma increased gradually, whereas it remained at low levels in III-IV patients. By contrast, IL-4 decrease was more pronounced in III-IV patients. Increase in CD4+CD25+high T cells occurred early in I-II patients but was delayed in III-IV patients. IL-10-producing T cells increased gradually in both groups but were in a lower proportion in III-IV patients. Conclusion: A T helper type 2 (Th2)-to-Th1 switch occurs during ultra-rush VIT, in parallel with natural and acquired regulatory T cell increase. These events occur earlier and at a higher level in less severe subjects, suggesting that VIT tolerance induction is easier to achieve in these patients.