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Atopic dermatitis is a frequent, relapsing, chronic inflammatory skin condition with a deep negative impact on quality of life. Three are the major pathological factors driving its complex pathogenesis: the skin barrier disruption, the altered Th2 cell response and itching. Current management of the disease is often unsatisfactory, unable to induce a complete resolution of signs and symptoms or at least a significant clinical improvement with adequate patient satisfaction.We report the case of a 57-year-old man with severe chronic atopic dermatitis for at least 40 years irresponsive to traditional therapies. The patient was treated in the past with different standard therapeutic regimens without satisfactory and lasting results.The diagnosis of AD was based on the revised criteria of Hanifin and Rjika and the Scoring Atopic Dermatitis was assessed together with laboratory evaluation.He received off-label omalizumab (300 mg subcutaneous injection repeated at 2-week intervals for six months).Scorad and laboratory findings were assessed montly and demonstrated a progressive decrease (SCORAD and ECP levels) togheter with general clinical improvement. Omalizumab, in our patient, determined a significant symptomatic improvement, assessed by SCORAD, simultaneously with a progressive decline in ECP serum levels, whit no side effects, confirming the substantial safety of the drug.The satisfactory response to omalizumab after the failure of all previous traditional treatments, confirms the efficacy of this biological drug in the therapy of refractory AD with high IgE levels and increased ECP serum levels. The lesson learnt from this case report is that Omalizumab represent an effective and safe alternative to traditional therapies in patients with severe irresponsive atopic dermatitis.