Clinical guidelines recommend add-on therapy with long-acting beta2-agonists (LABA) in patients with mild-to-moderate persistent asthma whose disease is not adequately controlled with inhaled corticosteroids (ICSs) alone. For those achieving control with add-on therapy, careful reduction in ICS dose followed by withdrawal of LABA is recommended. This study was designed to compare asthma-related outcomes in patients receiving fluticasone propionate/salmeterol combination (FSC) who stepped down to a lower dose of FSC versus those who stepped down to fluticasone propionate (FP) at the same dose of FP. A retrospective observational cohort study was performed using two large health insurance claims databases spanning from January 2000 to June 2007. Subjects were age > or =12 and <65 years, had a diagnosis of asthma (International Classification of Diseases [ICD-493.xx]), and who within 1 year of initiating FSC either stepped down to a lower dose of FSC ("FSC patients") or to FP only at the same dose of FP ("FP patients"). FSC and FP patients were matched based on propensity scores to control for potential differences in baseline demographic and clinical characteristics and preindex asthma-related and costs. Of 4350 subjects identified, 3881 stepped down to a lower dose of FSC and 469 stepped down to FP. After matching, there were 447 pairs of FSC and FP patients. FSC patients had 30% fewer prescriptions for short-acting beta-agonists, a 26% lower risk of receiving systemic corticosteroids, and a 48% lower risk of asthma-related hospitalization or Emergency Department visit during follow-up. Stepping down to FP monotherapy is associated with worsening asthma symptoms and greater risk of severe asthma-related exacerbations compared with staying on FSC at a lower ICS dose.