Physical exercise is a common trigger for bronchial asthma. We evaluated the preventive effect on exercise-induced bronchospasm (EIB) of a single 42 micrograms dose of salmeterol, a uniquely long-acting inhaled bronchodilator, and compared salmeterol with 180 micrograms albuterol in two independent, randomized, double-blind, placebo-controlled studies involving 161 subjects. Three exercise challenges were conducted over 12 h, and bronchoconstriction following the serial challenges was assessed as change in FEV1 compared with predose values. The mean maximal percentage decrease in FEV1 after the three exercise challenges was 5% at 0.5 h, 8% at 5.5 h, and 13% at 11.5 h postdose in the salmeterol group compared with 7, 25, and 27%, respectively, in the albuterol group and 27, 27, and 26%, respectively, in the placebo group (p < 0.001, overall treatment difference). Albuterol provided complete protection against EIB (defined as < 10% decrease in FEV1 compared with predose values) only after the first exercise challenge, but salmeterol continued to provide complete protection in the majority of subjects after each exercise challenge: 80% (44 of 55) at 0.5 h, 70% (37 of 53) at 5.5 h, and 55% (29 of 53) at 11.5 h. Electrocardiographic monitoring revealed no clinically significant changes in any treatment group 15 and 30 min following each exercise challenge. In summary, these data demonstrate that salmeterol is effective against EIB and that a single 42 micrograms dose can prevent EIB for up to 12 h.