The National Asthma Education and Prevention Program guidelines define asthma severity before treatment by lung function and symptoms. It has been assumed, but not demonstrated, that improvement in these measures would translate into improvement in health-related quality of life (HRQL). Because HRQL is an important outcome in asthma management, we asked what are the determinants of HRQL? To address this question, we retrospectively analyzed HRQL data, as measured by the Juniper Asthma Quality of Life Questionnaire, in subjects with mild versus moderate-severe asthma from two clinical trials. We examined whether these traditional clinical outcomes have different relationships to HRQL depending on asthma severity. We also assessed whether the relationship between clinical outcomes and HRQL in subjects with moderate-severe asthma would change when subjects improved to mild-moderate disease with controller medication treatment. Lung function was not an independent predictor or determinant of HRQL at any level of asthma severity, whereas intensity of shortness of breath predicted HRQL at all levels of asthma severity. Rescue beta-agonist use independently predicted HRQL in subjects with mild asthma, but not in those with moderate-severe asthma. In subjects with moderate-severe asthma who improved to mild-moderate disease with controller treatment, rescue beta-agonist use predicted HRQL. We conclude that the independent determinants of HRQL vary according to asthma severity and change with asthma treatment.