Omalizumab, a humanized monoclonal anti-IgE antibody, has largely demonstrated its efficacy in severe allergic asthma. There are limited data about the effectiveness of omalizumab in patients with non-atopic severe persistent asthma. In this study, we aimed to determine the effect of omalizumab in patients with non-atopic severe asthma and compare the data obtained with those in patients with allergic severe asthma. This study was an observational, retrospective, tertiary single-center study that assessed and compared the clinical outcome of adult patients with severe asthma (165 atopic and 41 non-atopic) who have been on omalizumab for one year or longer between January 2008 and January 2020. Effectiveness was assessed by considering symptom scores (GINA symptom control score), daily systemic corticosteroids (SCS) dosage, blood eosinophil counts, pulmonary function, and number of severe exacerbations and hospitalizations within the last one year. Omalizumab exhibited significant improvement in the clinical status of non-atopic asthma patients as measured by GINA symptom score [decreased from 3.77 ± 0.63 to 1.36 ± 1.27 (p<0.001)], the number of emergency room visits for asthma [decreased from 11.25 ± 14.69 to 0.25 ± 0.55 (p<0.001)], and the number of hospitalizations [decreased from 1.17 ± 2.87 to 0.14 ± 0.36 (p= 0.036)]. These results were not significantly different from those obtained in allergic asthma patients. FEV1 improved significantly from 2.08 ± 0.86 to 2.14 ± 0.84 (p= 0.041) and oral corticosteroid doses decreased significantly from 1.67 ± 7.49 to 0.46 ± 2.74 (p= 0.015) in the only atopic group. Omalizumab, which is a proven and effective treatment option for allergic asthma, may also be an efficacious alternative option in non-atopic severe asthma.