Omalizumab is a recombinant humanized monoclonal antibody targeting the high-affinity Fc receptor of IgE, registered for the treatment of chronic spontaneous urticaria and severe allergic asthma. We present a case series of nine patients with atopic dermatitis (AD) treated off-label with omalizumab and a systematic review of the existing literature. Patients were selected consecutively from a tertiary dermatological referral center during a 5-year period. All patients were treated with omalizumab at a starting dose of 300 mg subcutaneously every 4 weeks. Systematic literature searches were performed in PubMed, Web of Science, EMBASE, and ClinicalTrials.gov to identify any study (case reports, case series, and controlled trials) evaluating the effect of treatment with omalizumab in AD. Based on physicians' assessment, 50% of our patients had a good or excellent response to treatment with omalizumab; a further 12.5% had a moderate response, while 37.5% experienced no response or deterioration of symptoms during treatment. Treatment was generally well tolerated. Twenty-six studies with a median of four patients each (range 1-21), comprising 174 patients, were included in the systematic review. Summed over all studies, a total of 129 patients (74.1%) experienced a beneficial effect of treatment ranging from little to complete response. Omalizumab appears to be a safe and well tolerated, however expensive, treatment with some clinical benefit in patients with severe recalcitrant AD. Recommendation for use in clinical practice awaits evidence from larger randomized controlled trials.