Background The efficacy and safety of the aerosol metered-dose inhaler (MDI) formulation of salmeterol for asthma symptoms have been established. Recently, salmeterol has been introduced as a micronized powder formulation administered via a breath-activated multidose powder inhaler (Diskus). Objective A multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled study involving 498 adolescents and adults with mild-to-moderate asthma was conducted to compare the efficacy and safety of salmeterol powder 50 μg twice daily via Diskus, salmeterol aerosol 42 μg twice daily via MDI, and placebo. Methods Patients were randomized to one of the three treatment groups for 12 weeks. Efficacy was assessed by serial measurements of forced expiratory volume in one second (FEV 1) over 12 hours, daily peak expiratory flow (PEF), self-rated asthma symptom scores, nighttime awakenings, and supplemental albuterol use. Safety of each treatment was evaluated by monitoring vital signs, electrocardiograms, Holter monitoring, and occurrence of adverse events. Results As compared with placebo, both salmeterol powder and aerosol produced significant improvement in FEV 1 and PEF and decreased nighttime awakenings and supplemental albuterol use. There were no significant differences in the efficacy of the two salmeterol formulations. The magnitude of improvement in pulmonary function was undiminished over the 12-week study. Both formulations of salmeterol were well tolerated, with safety profiles not significantly different from placebo. Conclusion Results of this study indicate that salmeterol, administered either as a powder 50 μg twice daily via Diskus or as an aerosol 42 μg twice daily via MDI, produces clinically significant and comparable improvement in pulmonary function and is well tolerated in patients with mild-to-moderate persistent asthma.