It has always been controversial whether a single allergen performs better than multiple allergens in polysensitized patients during the allergen-specific immunotherapy. This study aimed to examine the clinical efficacy of single-allergen sublingual immunotherapy (SLIT) versus multi-allergen subcutaneous immunotherapy (SCIT) and to discover the change of the biomarker IL-4 after 1-year immunotherapy in polysensitized children aged 6-13 years with allergic rhinitis (AR) induced by house dust mites (HDMs). The AR polysensitized children (n=78) were randomly divided into two groups: SLIT group and SCIT group. Patients in the SLIT group sublingually received a single HDM extract and those in the SCIT group were subcutaneously given multiple-allergen extracts (HDM in combination with other clinically relevant allergen extracts). Before and 1 year after the allergen-specific immunotherapy (ASIT), the total nasal symptom scores (TNSS), total medication scores (TMS) and IL-4 levels in peripheral blood mononuclear cells (PBMCs) were compared respectively between the two groups. The results showed that the TNSS were greatly improved, and the TMS and IL-4 levels were significantly decreased after 1-year ASIT in both groups (SLIT group: P < 0.001; SCIT group: P < 0.001). There were no significant differences in any outcome measures between the two groups (for TNSS: P > 0.05; for TMS: P > 0.05; for IL-4 levels: P > 0.05). It was concluded that the clinical efficacy of single-allergen SLIT is comparable with that of multi-allergen SCIT in 6-13-year-old children with HDM-induced AR.