More information is needed on asthma control and health-related quality of life (HRQoL) in smokers with severe asthma. The main study objective was to characterize the association of HRQoL and disease control with cigarette smoking in individuals with severe asthma. A secondary objective was to analyze subject characteristics according to asthma onset: asthma that developed before smoking initiation versus asthma that developed after smoking initiation. This cross-sectional study included subjects with severe asthma aged 18-65 years. HRQoL was assessed using the Asthma Quality of Life Questionnaire (AQLQ) and asthma control was assessed using the Asthma Control Test (ACT) and Global Initiative for Asthma (GINA) criteria. Of the 87 patients studied, 58 (66.7%) were classified as asthmatics who had never smoked and 29 (33.3%) as asthmatics with smoking exposure. The proportion of subjects with uncontrolled asthma was higher in the asthma and smoking group (GINA criteria: P=0.032 and ACT criteria: P=0.003. There were no between-group differences in overall AQLQ score (P=0.475) or AQLQ domain scores (P>0.05). Fifty-eight subjects (66.7%) were nonsmokers, 20 (23%) had asthma onset before smoking, and 9 (10.3%) had asthma onset after smoking. Asthma onset before smoking was associated with uncontrolled asthma (P=0.013). In subjects with severe asthma, smoking was associated with a higher rate of uncontrolled disease but not with HRQoL scores.