Recent double-blind placebo-controlled trials for perennial allergic rhinitis have all clearly shown the efficacy of immunotherapy. Although several mechanisms for the clinical efficacy of immunotherapy have been proposed, the exact mechanisms related to the clinical effect still remain unclear. Since immunotherapy is a form of systemic treatment and its clinical benefit is likely to be, at least in part, a consequence of its systemic effects on different phases of immunological events, our study focused exclusively on several immunological parameters in serum. A total of 47 patients with perennial allergic rhinitis due to Dermatophagoides farinae enrolled in this prospective study. Venous blood was collected for determination of specific immunoglobulin (Ig)E, specific IgG4, soluble interleukin-2 receptor (IL-2R), interleukin-4 (IL-4), soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1), six times from 20 untreated patients and 27 patients on immunotherapy, at enrolment, and 1, 2, 3, 5, and 10 years after enrolment. No specific IgE, IgG4, soluble IL-2R, IL-4 and soluble ICAM-1 levels changed significantly for a span of 10 years in the untreated patients. By contrast, immunotherapy affected serum levels of specific IgE, specific IgG4, soluble IL-2R, IL-4 and soluble ICAM-1, but not of soluble VCAM-1. The rates of increase in specific IgG4 and the rates of decrease in soluble IL-2R were correlated with the rates of decrease in symptom scores during the first 3 years, but not 5 and 10 years after the course of immunotherapy. On the other hand, the rates of decrease in specific IgE, IL-4 and soluble ICAM-1 were significantly correlated with the rates of decrease in symptom scores at 5 and 10 years, but not during the first 3 years. Each immunological modulation by immunotherapy was likely to be involved in the working mechanism related to clinical efficacy at different phases of immunotherapy.