Background 49% of clinically diagnosed allergic rhinitis (AR) patients are sensitized to house dust mite (HDM). If allergen avoidance and symptomatic medication fail, allergen immunotherapy may be indicated. We investigated safety and tolerability of HDM-sublingual immunotherapy HDM SLIT-tablets in adults in daily clinical practice in the Netherlands. Methods Daily intake of 12 SQ-HDM SLIT-tablet was investigated in the prospective, multi-center, observational study. It comprised 4 consultations in 1 year. Data on safety, tolerability, treatment satisfaction, symptomatic medication, compliance, and clinical effectiveness (Control of Allergic Rhinitis and Asthma Test; CARAT) were collected. Descriptive and longitudinal regression data analysis was performed. Results 415 adult patients, mean age 36.6 years, 61.4% female, 36% asthmatic were included. 65.3% of patients experienced possibly-related adverse events (AEs). These mostly mild (67%) AEs comprised: oral allergic reactions (58.6%), respiratory (12.4%) and gastrointestinal symptoms (9.4%). 60 (14.5%) patients stopped due to AEs and 76 (18.3%) for non-AE reasons. Mean CARAT scores improved clinically significant by 6 points and symptomatic medication use decreased from 96.1% to 77.4%. 74.5% of patients tolerated the treatment well. Most patients were compliant (>86.5%) and patients (62.4 %) and investigators (69.4%) were satisfied with treatment. Conclusions HDM-SLIT-tablet is a safe and well-tolerated AR treatment. AEs occur often but are mostly mild and decreasing during the first year. CARAT scores improved and symptomatic medication use decreased suggesting better control of AR with HDMSLIT-tablet treatment. Compliance, tolerability, and treatment satisfaction are good. However, patient follow-up and compliance remain important points of attention when starting HDM SLIT-tablet.