Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo‐controlled, randomized, double‐blind, two‐period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise‐induced asthma. The patients received placebo or roflumilast (500 μg/day) for28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1,14, and 28.FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1,3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)‐stimulated tumor necrosis factor alpha (TNF‐α) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV₁ after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF‐α level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise‐induced asthma. This result was accompanied by a significant reduction of TNF‐α levels ex vivo. Treatment with roflumilast was safe and well tolerated.