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Biologic drugs have been shown to reduce asthma exacerbations, improve lung function and quality of life, reduce oral corticosteroid use in appropriately selected patients. Mepolizumab has been demonstrated to have a safety profile that is similar to placebo, however, when present side effects may lead to treatment discontinuation. Among these, headache is one of the most common. We hereby describe the case of a never-smoking male patient with an eosinophilic corticosteroid-dependent severe asthma. He displayed well controlled comorbidities and good adherence to the inhaled therapy. Mepolizumab was started in 2017 with an initial remarkable clinical improvement. After three doses of biologic therapy, he reported a severe orthostatic headache associated with vomiting, unresponsive to analgesic drugs, that required hospitalization. No other cause than treatment with Mepolizumab was found to be plausibly associated with this new-onset headache. The therapeutic regimen was modified by administering Mepolizumab for two consecutive months alternated with a one-month break. The patient did not experience any further episodes of headache, while maintaining a good and stable control of his asthma. We were able to taper oral corticosteroids, and no flares-ups occurred in the following 5 years. Our experience indicates that a tailored strategy for managing severe asthmatic patients, who have experienced side effects from biologic drugs, can be effective in maintaining drug efficacy while minimizing side effects. Further studies on a larger number of patients are required to demonstrate whether the positive outcomes here described are replicable on a larger scale. [ABSTRACT FROM AUTHOR]