Background: Real-world data of the subcutaneous immunotherapy (SCIT) with semi-depot house-dust mite (HDM) allergen extract (a HDM allergen extract that contains a 50%-50% mixture of Dermatophagoides pteronyssinus and Dermatophagoides farina) for allergic rhinitis and asthma was unavailable in China until recently. Aim: To investigate the effectiveness and safety of a HDM-SCIT for allergic rhinitis and asthma in Chinese patients. Methods: A multicenter, single-arm, open-label, self-controlled study. Chinese patients with allergic rhinitis or allergic asthma and with a history of symptoms from HDM exposure were included and received allergen-specific immunotherapy for 1 year by subcutaneous injection of HDM-SCIT. The primary outcome measure was the percentage of patients with an improvement in symptom severity assessed at 12 months after initiation of the treatment. The occurrence of adverse events and compliance of treatment were also evaluated. Results: A total of 272 outpatients were included for effectiveness analysis. The subject-evaluated improvement rate in the visual analog scale (VAS) was 76.1% and 71.3% at 6 and 12 months, respectively; corresponding values for investigator-evaluated VAS were 77.9% and 71.7%, respectively (p < 0.0001). Symptom score changes were -2.43 and -3.79 at 6 and 12 months, respectively (both p < 0.0001); the VAS improvement rate and symptom score change did not differ significantly between children and adolescents and/or adults. Good injection schedule adherence was found in 98.8% of the patients. No study drug-related serious adverse events or serious systemic allergic reactions occurred. Conclusion: HDM-SCIT was safe and effective in the treatment of allergic rhinitis and asthma in a Chinese population, with good compliance.