The development of tolerance to the bronchodilator effects of beta2-agonists used in asthma therapy has been the subject of debate. We conducted two placebo-controlled crossover studies to assess the bronchodilator response to a short-acting beta2-agonist before and after chronic therapy with salmeterol. Patients in one study were corticosteroid-naive; patients in the other study were using inhaled corticosteroids. Changes in FEV1 after cumulative doubling doses of inhaled albuterol were assessed after a 2-wk beta-agonist washout period, before administering study medication on Day 1, and again after 28 d of therapy. Ipratropium bromide was provided as rapid-relief treatment for asthma, and use of any beta2-agonist except the study treatment was prohibited. On both assessment days for salmeterol, and during placebo administration periods, significant increases from predose FEV1 values were observed beginning with the lowest dose of albuterol and continuing throughout the dose-response assessment (p </= 0.001). These increases in FEV1 were maintained for 6 h after the last dose of albuterol (p < 0.05). There were no statistically significant differences in the albuterol dose response following salmeterol or placebo. These studies indicate that irrespective of concurrent corticosteroid treatment, chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol.