Background: Patients with mast cell activation syndrome (MCAS) can be refractory to standard antimediator therapy. Alternative treatment options to reduce disease burden and improve quality of life are needed. Objective: To compile the evidence that supports the use of omalizumab for patients with refractory MCAS. Methods: Through a systematic review of the PubMed database, we compiled and analyzed the characteristics of patients with refractory MCAS, unresponsive to histamine 1 receptor antihistamines plus another antimediator agent (refractory MCAS), and who were treated with omalizumab. We categorized the clinical response to omalizumab as no, partial, or complete response. Results: We identified nine studies that described a total of 28 patients (median age, 48 years; males, 54%) with refractory MCAS. Twenty-one patients (75%) had nonclonal MCAS, and seven patients (25%) had clonal MCAS. The omalizumab dose ranged from 150 mg every 4 weeks to 300 mg every 3 weeks, with the most common dose being 150 mg every 2 weeks. Most patients had a partial response (61%), and five patients achieved a complete response. Omalizumab was successful in ameliorating anaphylaxis and allowed for discontinuation of systemic glucocorticoids in two of three patients. The response pattern was not influenced by sex or mast cell clonality, but a complete response was reported more commonly among receivers of a higher omalizumab dose (≥300 mg/month). No major adverse events were reported. Conclusion: The majority of patients with refractory MCAS reported in the literature had a reduction in mast cell mediator-related symptoms with the addition of omalizumab.