Background: The real-life data on the effectiveness and safety of omalizumab in chronic spontaneous urticaria (CSU) with validated methods are scarce. There is also a lack of information on the use of combination treatments. Methods: A retrospective cohort study was done to evaluate the effectiveness and safety of omalizumab in real-life conditions. The patients with CSU treated with omalizumab between 2015 and 2018 were included. The response to therapy was evaluated using urticaria activity score over 7 days (UAS7) and urticaria control test (UCT). Results: A total of 106 patients were included. A complete response (CR) (UAS7:0) and a well-controlled activity (WCA) (UAS7:1 to <6) were observed in 50 (47.2%) and 35 (33%) patients, respectively. The number of patients with an UCT score >= 12 was also significantly increased. Higher rates of CR/WCA were observed with omalizumab monotherapy compared to combination with antihistamines. The combination of dapsone, colchicine, and omalizumab provided additional benefit in a small group. Conclusion: Treatment with omalizumab provided a rapid and sustainable improvement in real-life settings. The use of omalizumab as monotherapy or combined with antihistamines does not show differences in the treatment response. The combination of omalizumab with immunomodulatory agents might be of benefit in selected cases.