Background: Several foreign studies have shown long-term efficacy of sublingual immunotherapy (SLIT), but data on the long-term efficacy of SLIT in China are still lacking. Objective: We aimed to prospectively evaluate the long-term efficacy of a 2-year SLIT with Dermatophagoides farinae(D. farinae) drops in mono- and polysensitized children with allergic rhinitis (AR). Methods: Eighty house dust mite (HDM)-sensitized children (aged 4–11 years) with AR were enrolled in this prospective study. There were 40 children in both the monosensitized (to HDM only) and polysensitized groups. Both groups were treated with standardized SLIT (D. farinae drops) for 2 years, combined with pharmacotherapy according to their individual requirements, and were followed up for 7 years. A combined symptom and medication score (CSMS) was assessed and compared between the 2 groups during and after SLIT. Safety was evaluated based on adverse events (AEs). Results: There were 31 (77.5%) monosensitized and 29 (72.5%) polysensitized children who completed the study. After 2-year SLIT, the CSMS of 2 groups significantly decreased compared to baseline. The improvement persisted during the first 5 years at each visit, with a significant difference (all p < 0.01). In the monosensitized group, the CSMS significantly increased during the 6th and the 7th year compared to year 2 (both p < 0.05). Meanwhile, the polysensitized group showed a significant worsening of CSMS from the 5th to the 7th year (all p < 0.05). Furthermore, there was a statistical difference between the 2 groups in the 5th year of the study (p < 0.05). No severe AEs were reported. Conclusions: The study confirmed the long-term effects which lasted for 7 years after 2-year SLIT in mono- and polysensitized children. Compared with the polysensitized children, the monosensitized children noted a more sustained benefit.