Background: Asthmatic smokers are a distinct phenotype of asthma. There is a lack of specific information about the treatment of asthma in smokers. The purpose of this study was to compare the effects of inhaled corticosteroid (ICS) on asthmatic smokers and non-smokers. Results: The present observational, cross-sectional study was conducted at the Chest Department in Assiut University Hospital, during the period from August 2018 to January 2020. Hundred and seventeen asthmatic patients (42 smokers, 30 ex-smokers, and 45 non-smokers) were assessed using an asthma control questionnaire (ACQ), spirometry, sputum cytology, and serum periostin and eotaxin-2 to compare between a patient on inhaled corticosteroid for at least 3 months and patients who do not receive any form of corticosteroid. Asthmatic smokers had poor response to ICS and had insignificant improvement as regard all parameters. However, asthmatic exsmokers had a partial response to ICS. They had higher post-bronchodilator FEV1 in comparison to those who did not receive ICS. Asthmatic non-smokers on ICS showed the best response as they were well controlled as regard ACQ. Moreover, they had higher post-bronchodilator FEV1/FVC, post-bronchodilator FEV1, and post-bronchodilator FEF25-75, and lower sputum eosinophils and neutrophils. Conclusion: Smoking adversely affects the course and response to ICS therapy in asthma. Trial registration: Interrelation between bronchial asthma and smoking: ClinicalTrials.gov ID: NCT03207620. Registered 27 June 2017.