We designed a cluster schedule of immunotherapy for patients allergic to Dermatophagoides pteronyssinus which showed good safety and clinical efficacy. Here we compare the in vivo and in vitro changes with those of a conventional schedule in a controlled trial. Sixty-three patients were randomized as follows: 29 were treated with the cluster schedule, 15 with a conventional schedule and 19 received no immunotherapy. A standardized extract was used. Changes in in vivo parameters (skin prick test and conjunctival provocation test) and in in vitro parameters (IgE, IgG, IgG1 and IgG4 for the complete extract, Der p 1 and Der p 2) were measured before immunotherapy (T0), on reaching maintenance phase (T1), and after 6 (T2), 12 (T3) and 18 months of maintenance (T4). Cutaneous reactivity showed a significant decrease from T1 in both the cluster and conventional schedules, and conjunctival reactivity was also significantly lowered from T1 in these groups. Specific IgE decreased and specific IgG, IgG1 and IgG4 increased significantly from T1 in the cluster and conventional schedules. Neither of these parameters showed any changes in the group without immunotherapy. In conclusion, our cluster schedule induced changes in cutaneous and conjunctival reactivity and in immunological parameters that were similar to those achieved with the conventional schedule; these changes did not appear in patients who did not undergo immunotherapy.