Summary Background Vernal keratoconjunctivitis (VKC) is a rare, recurrent form of ocular allergy that can be refractory to topical and systemic treatment. It typically presents as acute and chronic keratoconjunctival inflammation that may lead to visual impairment due to corneal ulcers and scaring. Patients often suffer from atopic IgE-driven comorbidities, especially atopic eczema. Children are frequently affected and often do not tolerate topical treatment well, especially if photophobia and pain impair therapy adherence. We present three children with severe VKC who were not controlled by first- and second-line topical and systemic therapy and finally responded to treatment with the monoclonal anti-IgE antibody omalizumab as third-line treatment. Methods and results We retrospectively analyzed three patients with VKC having failed response to first- and second-line treatment. All three boys had very early allergic rhinoconjunctivitis from age 1–3 with polysensitization: birch, grass pollen, house dust mite, and/or pets. All received subcutaneous or sublingual immunotherapy (SCIT/SLIT) for birch and/or grass pollen without major success. Two patients had comorbidities: allergic asthma and severe atopic dermatitis (AD). For at least 6 months after the first administration, monoclonal anti-IgE antibody omalizumab (150 or 300 mg) was administered subcutaneously every 2–6 weeks in all patients achieving improvement of the clinical grading scale from VKC grade 3–4 to grade 1–2. One patient had a relapse mainly of his AD and achieved complete control of AD and VKC by introduction of dupilumab. Conclusion Although the clinical benefit of omalizumab in asthma and chronic spontaneous urticaria (CSU) has been established in several clinical trials, there are very little data about its effect on severe VKC. In addition to few previously reported cases we can report the rapid effectiveness of omalizumab in VKC clinically and in terms of quality of life. Randomized trials are needed to include omalizumab in third-line treatment of VKC for prevention of visual impairment and further sequelae such as corneal damage.