Alpha-gal syndrome (AGS) is a unique food allergy to red meat and products containing mammalian-derived ingredients. Patients can develop AGS after decades of immunologic tolerance of beef, pork, lamb, gelatin and the allergy appears to develop following ectoparasitic tick bites. A subgroup of patients with AGS continue to remain symptomatic despite an appropriate avoidance diet and we assessed whether treatment with omalizumab could improve their symptoms. Qualifying patients with AGS had urticaria activity score summed over 7 days (UAS7) to assess the itch severity and hive count once daily before, 4 weeks after, and 12 weeks after omalizumab therapy (300 mg every 4 weeks). Over a 2 year period, fourteen patients with AGS elected to begin omalizumab treatment for chronic urticaria despite an appropriate mammalian avoidance diet. Mean UAS7 scores before treatment were 23.3 (17.8-29.4) and at 4-weeks of treatment the mean UAS7 score declined to 4.2 (1.9-7.5). By 12 weeks of omalizumab therapy, mean UAS7 scores were 0.4 (0-1.1). Patient-reported improvment in symptoms following accidental exposure to mammalian ingredients (e.g., butter, dairy) was noted in 12 of 14 (86%) cases with several noting no symptoms despite intential allergen consumption while on omalizumab. Omalizumab appears to effectively treat chronic, spontaneous urticaria developing after a new-onset food allergy and may be associated with improved tolerance of accidental exposure to the relevant allergen, alpha-gal. Anti-IgE therapy could offer adjunctive treatment for food allergy when avoidance diet does not sufficiently control symptoms.