Although the efficacy of allergen-specific sublingual immunotherapy (SLIT) is now accepted, the underlying mechanisms remain elusive. Such mechanisms are better documented in the case of subcutaneous immunotherapy (SCIT). In order to understand the T-lymphocyte response in patients receiving SLIT, we compared children with respiratory disease monosensitized to Dermatophagoides pteronyssinus receiving SLIT or SCIT over a 2-yr period. Peripheral blood was obtained before beginning immunotherapy, and after 3 months, 1 yr and 2 yr. Total IgE, specific IgE and IgG4 to D. pteronyssinus were determined in serum. T-cell markers (CD3, CD4, CD8, CD25) and intracellular cytokine production (TNF-alpha, IL-2, IL-4 and IFN-gamma) were determined in peripheral blood mononuclear cells (PBMC) by flow cytometry. No differences between SCIT and SLIT were detected in the clinical variables or in the subjective evaluation. Although an increase in specific IgE and IgG4 was only detected in SCIT, a significant decrease in the specific IgE/IgG4 ratio was found in both groups. SCIT and SLIT experienced an increase in the CD4/CD8 ratio over time, but an increase in the CD4(+)CD25(+) and a decrease in the CD8(+)CD25(+) subsets were only found with SCIT. A slight shift from a Th2 to a Th1 pattern, measured by the IFN-gamma/IL-4 ratio, was only detected in the CD4 T cells with SCIT. A decrease in both groups was found in TNF-alpha and IL-2 production over time. Children with respiratory allergic diseases receiving SCIT or SLIT had a different immunologic response in peripheral blood during treatment, though the clinical improvement was similar. Whether SLIT induces a mucosal protective response should be studied.