BACKGROUND Exercise-induced bronchospasm (EIB) is a common problem in children with asthma. Pretreatment with the beta2 (beta 2)-adrenoreceptor agonist albuterol is effective for preventing EIB, but is recognized as providing only short-term (2 to 3 hour) protection. OBJECTIVE To evaluate the 12-hour efficacy and safety of single doses of 25 micrograms and 50 micrograms of salmeterol powder administered via Diskus inhaler versus albuterol aerosol via pressurized metered-dose inhaler and placebo in preventing EIB in asthmatic children. METHODS A randomized, double-blind, placebo-controlled, double-dummy, single-dose, four-way crossover study was conducted in pediatric patients (4 to 11 years of age) demonstrating EIB and mild-to-moderate asthma. Serial forced expiratory volume in 1 second (FEV1) was measured before and after standard treadmill exercise at hour 1, hour 6, and hour 12 after administration of 25 micrograms or 50 micrograms salmeterol powder, 180 micrograms albuterol aerosol, or placebo. Adverse events were recorded. RESULTS After completion of the hour 1 exercise challenge, mean minimum % predicted FEV1 was significantly higher following albuterol (91.3%) than for placebo (75.3%) and for both dosages of salmeterol (86.9% and 85.8% for salmeterol 25 micrograms and 50 micrograms, respectively; P < or = .026). After completion of both the hour 6 and hour 12 exercise challenges, the 50-microgram salmeterol treatment produced a significantly higher mean minimum percent of predicted FEV1 (90.6% and 87.3% predicted, respectively) than the mean minimum percent of predicted FEV1 for placebo or albuterol (73.8% to 78.4% of predicted; P < or = .041). At hour 6, the 25-microgram salmeterol treatment was not significantly different from albuterol or placebo. At hour 12, the 25-microgram salmeterol treatment mean minimum percent of predicted was significantly higher than albuterol (87.9% versus 73.8% of predicted; P = .006) and there was also a trend toward significance over placebo (76.9% predicted; P = .056). At all exercise periods, no statistically significant differences in spirometry values were observed between the two salmeterol treatment groups. Safety profiles were similar among treatments, including placebo. No drug-related adverse events or withdrawals due to adverse events occurred. Changes in laboratory values, vital signs, 12-lead ECGs, and physical examinations were unremarkable. CONCLUSIONS A single 50-microgram dose of salmeterol powder provided effective and safe protection against EIB for at least 12 hours in asthmatic children and provided a significantly more prolonged effect than albuterol aerosol (180 micrograms).