The clinical efficacy of sublingual immunotherapy (SLIT) has been demonstrated, but its mechanism of action is still controversial. The most recent experimental observations suggest that a critical role in the modulation of immune response is sustained by Th2 cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, by co-stimulatory molecules, such as CD40 on B cells, and by hormones and neuropeptides. To better understand whether SLIT affects immune responses we used a double-blind placebo-controlled design. Eighty-six children with mild asthma due to allergy to Dermatophagoides pteronyssinus (33 of whom also had rhinoconjunctivitis) were randomly assigned SLIT (n = 47) or placebo (n = 39). We assessed symptom scores using diary cards of each patient and determined the expression of CD40 on B cells and the serum concentration of ECP, IL-13, prolactin (PRL) and ACTH at enrolment and after 6 months of therapy. We observed a significant reduction in asthma and rhinitis scores in the immunotherapy group compared with the placebo group, no variation in CD40 and ACTH, but a significant decrease in ECP, IL-13 and PRL after 6 months of therapy (p <0.01). Our results confirm the efficacy and safety of SLIT, and lead us to believe that it could modulate the synthesis of Th2 cytokines, as revealed from the decrease of IL-13. In addition, the reduction of PRL might be a signal of reduced activation of T lymphocytes.