Background: Chronic spontaneous urticaria (CSU) is a skin disease with itchy hives and/or angio-oedema that last for at least 6 weeks without an obvious external trigger. Objectives: To determine the cost-effectiveness of omalizumab relative to standard of care (SoC; up to four times the daily dose of H1-antihistamines) in the Netherlands from a societal perspective. Methods: The Markov model used consisted of five health states based on Urticaria Activity Score over 7 days. Model settings and characteristics of the Dutch patient population were based on an online survey among clinical experts and were validated during an expert committee meeting. Transition probabilities were derived from the GLACIAL trial. Healthcare consumption, quality of life (using EuroQol-5D) and productivity losses were derived from a burden-of-illness study (ASSURE-CSU) among 93 Dutch patients. Healthcare consumption and productivity losses were evaluated using the Dutch costing manual. The comparator treatment was SoC, consisting of (updosed) antihistamines. A 10-year time horizon was used. Results: The incremental cost-effectiveness ratio (ICER) of omalizumab vs. SoC was €17 502 per quality-adjusted life-year (QALY) gained. Productivity costs played an important role in the value of the ICER; discarding productivity costs resulted in an ICER of €85 310 per QALY. Conclusions: Omalizumab is cost-effective compared with SoC. The outcomes of this study were used to establish omalizumab as third-line therapy in the Dutch treatment guidelines for CSU.