Introduction For moderate-to-severe persistent asthmatics that remain symptomatic despite their anti-inflammatory high dose inhaled corticosteroid treatment with inhaled long-acting beta2-agonist bronchodilator, the addition of subcutaneous Dupilumab, a fully human anti-interleukin-4 receptor alpha monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling, may provide additional efficacy in sub optimally controlled moderate-to-severe persistent asthmatics. Methods In this open labeled 16-week trial, 60 patients 12 years and older with symptomatic uncontrolled asthma were randomized to receive the addition of subcutaneous Dupilumab at a dose of 300mg every 2 weeks or to continue with their existing therapy. The endpoints of the trial included: FEV1, PEF am, PEF pm, albuterol use, exacerbations rates, and a Quality of life (QOL) questionnaire. Written consent was obtained. Results Mean efficacy measurements at 16 weeks revealed significant improvement in all parameters examined in the treatment group as add-on Dipulimab compared to the group without the add-on therapy. Analysis between both treatment groups revealed significant differences in all parameters monitored (FEV1, PEF am, PEF pm, albuterol use, exacerbations rates, nocturnal awakenings, limited activity, chest tightness, cough, wheezing, shortness of breath) in the group with the add-on Dupilumab. The addition of Dupilumab to the maintenance controller therapy is more effective than the maintenance therapy only. When Dupilumab is added to the maintenance controller therapy, all endpoints significantly improved. Conclusions The addition of subcutaneous Dupilumab has additive beneficial protective effects of bronchodilator, anti-inflammatory and anti-remodeling action, and is safer therapy given the long-term safety issues with high doses of inhaled corticosteroids.