Background: Group 2 innate lymphoid cells (ILC2s) are regarded as a novel population of lineage-negative cells that induce innate Type 2 responses by producing the critical Th2-type cytokines interleukin (IL)-5 and IL-13. ILC2s as key players in the development of allergic rhinitis (AR) have been proved, however, the effect of subcutaneous immunotherapy (SCIT) with dermatophagoides pteronyssinus extract (Der p-SCIT) on ILC2s in AR patients is not clear. This study aimed to investigate the response of ILC2s of peripheral blood in house dust mites (HDM)-sensitized Chinese patients with AR who received SCIT with Der P extract. Methods: Seven healthy controls without symptoms of AR who had negative reactions to any of the allergens from skin-prick testing, nine patients diagnosed with persistent AR according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, and 24 AR patients who received Der p-SCIT for 1.0-3.5 years were recruited for the study. ILC2s in the peripheral blood were evaluated using flow cytometry. The severity of their symptoms of all participants was rated based on the Total 5 symptom score. Results: Among 40 participants, 9 AR patients were assigned to the untreated group, 24 AR patients receiving Der p-SCIT were assigned to the immunotherapy group, and 7 healthy controls without symptoms of AR were assigned to healthy control group. The mean Total 5 symptom score of immunotherapy group was significantly lower than that of untreated group (4.3 +/- 1.4 vs. 10.1 +/- 2.5, P < 0.001). Similarly, the levels of ILC2s in the peripheral blood of immunotherapy group were significantly reduced compared with that in untreated group (P < 0.001), but were not significantly different from healthy controls (P = 0.775). Further subgroup analysis based on the duration of SCIT therapy (1.0-2.0 years [SCIT 1-2], 2.0-3.0 years [SCIT 2-3], and 3.0-3.5 years [SCIT 3-3.5]) showed that the percentage of ILC2s was not significantly different between SCIT 1-2, SCIT 2-3, and SCIT 3-3.5 groups (SCIT 1-2 vs. SCIT 2-3 : P = 0.268; SCIT 1-2 vs. SCIT 3-3.5 : P = 0.635; and SCIT 2-3 vs. SCIT 3-3.5 : P = 0.787). Conclusions: The present study highlighted the suppression of Der p-SCIT on ILC2s in HDM-AR patients. ILC2s identified in peripheral blood can be used as an effective biomarker for Der p-SCIT.