OBJECTIVES: Current guidelines recommend inhaled corticosteroids (ICS) as first-line therapy in persistent asthma and the addition of long-acting ß-agonists (LABAs) in patients with moderate-to-severe disease. Our study objective was to assess the response of high-dose salmeterol/fluticasone combination (SFC) and low-dose SFC compared to a control group using a vast array of asthma-related health outcomes in a large cohort of patients with severe or difficult-to-treat asthma. METHODS: Three adult (°Ý18 years) cohorts from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) 3-year observational study were defined: patients on SFC Low-Dose (100/50 or 250/50 µg), patients on SFC High-Dose (500/50 µg), and patients on other medications (including salmeterol and fluticasone), but not on SFC. Using standard regression methods, we computed unadjusted and propensity score adjusted differences in 24 month outcomes between the treatment cohorts. RESULTS: After adjustment for confounding, the Low-Dose SFC cohort had higher asthma-related quality of life (P=0.0026), fewer asthma control problems (P=0.0001), similar rates of exacerbations (P=0.8932), marginally higher FEV1 (P=0.0777) and lower odds of having severe asthma (P=0.0454) compared with controls (patients never on SFC). After adjustment for confounding, the High-Dose SFC cohort had no difference in asthma-related quality of life, asthma control problems, or exacerbation rates (P=0.1879, 0.3015, 0.3560 respectively), higher FEV1 (P=0.0011), and higher odds of having severe asthma (P=0.0137). CONCLUSION: The results support evidence that some asthmatics achieve better control while taking low-dose SFC, but also suggest that high-dose SFC fails to provide clinically significant benefit in terms of most asthma-related health outcomes when compared to similar patients not taking high-dose SFC. These findings may highlight an unmet need in severe or difficult-to-treat asthma and call for alternative therapeutic approaches in those unable to attain asthma control with or without SFC.