Background anti-IgE (Omalizumab) is one of the targeted therapies for severe bronchial asthma. Its real-life safety is still under scrutiny. The aim of the study was to evaluate the persistent efficacy and safety of Omalizumab as a long-term treatment of severe bronchial asthma. Patients and methods A prospective cohort study was conducted on 74 patients who had severe bronchial asthma eligible for Omalizumab subcutaneous treatment with a long-term regular follow-up to evaluate the long-term safety and efficacy of Omalizumab. Results This study was conducted on 74 patients who had severe bronchial asthma: 33 patients (44.6%) were males with a mean±SD (37.2 ± 4), and 41 females (55.4%) with a mean±SD (35.9 ± 6). Those patients were eligible for Omalizumab treatment with a long-term regular follow-up (from 7 to 10 years) to assess the long-term safety of Omalizumab. Omalizumab treatment has a significant improvement in the clinical condition of severe bronchial asthma as it decreased the number of patients who used oral steroids from 63 patients (before starting treatment) to 6 patients after 6 months of treatment, and 2 patients after 12 months of the dose. The use of tiotropium bromide had a significant decrease because the number of patients fell from 61 patients (before the start of treatment) to 13 patients after 6 months. It also reduced the number of acute exacerbations of bronchial asthma from 7 times per year (before the start of treatment) to 3 times after 6 months, and 2 times after 12 months of treatment. Patients’ pulmonary functions (FEV1, FEV1/ FVC, PEFR) improved significantly from (43.7 ± 9, 52.3 ± 11, 51.1 ± 4) before starting Omalizumab treatment to (64.1 ± 11,71.3 ± 13, 68.2 ± 7) after 6 months of usage; and to (69.4 ± 12, 73.3 ± 14, 72.1 ± 6) after 12 months of treatment. Long-term use of Omalizumab has less severe side effects as 70% of patients had injection site reactions in the form of local tenderness and swelling, 24.3% had a headache, 12% had nausea, 9.4% had myalgia, and 17.5% had a fever while the serious side effects as cancer, anaphylaxis or myocardial infarction has not recorded. All the side effects occurred in the first year of treatment. Conclusion Long term use of Omalizumab in severe bronchial asthma management has persistent efficacy and no serious side effects such as cancer, myocardial infarction or anaphylaxis and has only minimal side effects that occurred mostly in the first year of Omalizumab treatment, meaning that the physician cannot stop giving