BACKGROUND In patients with asthma, particularly severe asthma, poor adherence to inhaled drugs negatively affects the achievement of disease control. A better adherence rate is expected in the case of injected drugs, such as omalizumab, as they are administered only in a hospital setting. However, adherence to omalizumab has never been systematically investigated. The aim of this study was to review the omalizumab drop-out rate in randomized controlled trials (RCTs) and real-life studies. A comparative analysis was performed between published data and the Italian North East Omalizumab Network (NEONet) database. RESULTS In RCTs the drop-out rate ranged from 7.1 to 19.4 %. Although the reasons for withdrawal were only occasionally reported, patient decision and adverse events were the most frequently reported causes. In real-life studies the drop-out rate ranged from 0 to 45.5 %. In most cases lack of efficacy was responsible for treatment discontinuation. According to NEONet data, 32 % of treated patients dropped out, with an increasing number of drop outs observed over time. Patient decision and lack of efficacy accounted for most treatment withdrawals. CONCLUSIONS Treatment adherence is particularly crucial in patients with severe asthma considering the clinical impact of the disease and the cost of non-adherence. The risk of treatment discontinuation has to be carefully considered both in the experimental and real-life settings. Increased knowledge regarding the main reasons for patient withdrawal is important to improve adherence in clinical practice.