Different molecular mechanisms may modulate sensitization and natural or induced tolerance to allergens. We have searched for differential mechanisms at humoral and cellular level in the olive pollen allergic response, checking the influence of exposure to allergens of subjects from an area with extremely high antigenic load during the pollen season. Sera and PBMCs were obtained during and outside the pollen season. Distinct Ig subtypes (total IgE and specific IgE, IgG4 and IgA), and Th1, Th2 and regulatory T cells (Treg) cytokines were analyzed in 5 groups of subjects: Group 1, non-allergic; Group 2, asymptomatic, sensitized to olive pollen; Group 3, allergic to pollen other than olive; Group 4, allergic to olive pollen (not treated); and Group 5, allergic to olive pollen, and getting specific immunotherapy. Asymptomatic subjects showed the highest total IgE levels. The major difference found between untreated and treated subjects was the high levels of non-inflammatory antibodies (IgG4) in treated Patients. The main result of cytokine analyses was the statistically significant decrease in TGF-β levels in untreated olive pollen allergic subjects (pollen season) compared with treated. A significant decrease in forkhead winged-helix transcription factor (FOXP3) mRNA expression (marker of regulatory response) and a lower presence of Treg cells in PBMCs of olive pollen allergic subjects was found. The results Point to a decrease in the cellular regulatory mechanisms mediated by TGF-β and FOXP3 in olive-pollen allergic patients that could be restored after specific-immunotherapy.