BACKGROUND: Allergic rhinitis (AR) is a chronic inflammatory disorder, and sublingual immunotherapy (SLIT) is an important therapy. However, SLIT exhibits a wide range of fluctuations and lacks objective monitoring indicators. Therefore, exploring biomarkers for early prediction of the efficacy of SLIT is urgently needed. METHODS: We recruited two independent cohorts. In the discovery cohort, house dust mite (HDM) -induced AR patients underwent SLIT for at least 1 year, and were categorized into response and no response groups based on early efficacy. Serum proteomics was conducted to detect variations in protein expression levels between the two groups. The candidate proteins were confirmed in the validation cohort with enzyme-linked immunosorbent assay (ELISA), and their predictive values and levels of change before and after treatment were evaluated. RESULTS: Serum proteomics identified a total of 113 differential proteins between the two groups, including 41 proteins upregulated and 72 downregulated in the no response group than the response group. The top 5 up- and down-regulated proteins were selected for further validation, and ELISA results revealed that serum CCL14, LTA4H, S100A11 and MMP9 levels were significantly elevated, and TGFBI and MASP1 were decreased in the response group than those in the no response group(P < 0.05). Moreover, receiver operating characteristic curves revealed that serum S100A11 and MMP9 exhibited greater ability in predicting the early effectiveness of SLIT (AUC > 0.7, P < 0.05). Furthermore, these two biomarkers exhibited significant reductions 1 year after SLIT, particularly in those patients who responded positively to the treatment (P < 0.05). CONCLUSION: Serum S100A11 and MMP9 have the potential to serve as biomarkers for early prediction of the effectiveness of SLIT and monitoring the therapeutic effects. The circulating proteomic alterations might contribute to guiding treatment and understanding the mechanism of SLIT in AR patients.