Roflumilast is an orally administered, selective phosphodiesterase 4 inhibitor that is a novel treatment for patients with severe chronic obstructive pulmonary disease (COPD). Across four randomized, double-blind, multinational trials in patients with moderate to severe or severe COPD, roflumilast 500 microg/day produced significantly greater improvements from baseline than placebo in pre- and post-bronchodilator forced expiratory volume in 1 second (FEV(1)). While mean increases in FEV(1) in roflumilast groups were small, they were in marked contrast to the decreases or negligible increase in FEV(1) in the placebo groups. In three of four trials, roflumilast significantly reduced the COPD exacerbation rate; in a pooled analysis of two 52-week trials, roflumilast was associated with a 17% reduction over placebo. Further randomized, double-blind, multinational trials compared roflumilast 500 microg plus salmeterol with placebo plus salmeterol and roflumilast 500 microg plus tiotropium bromide with placebo plus tiotropium bromide. In both trials, roflumilast plus long-acting bronchodilator produced significantly greater increases in pre- and post-bronchodilator FEV(1) than placebo plus long-acting bronchodilator. Roflumilast had an acceptable tolerability profile. In a pooled analysis of two trials, 19% and 22% of roflumilast and placebo recipients had serious adverse events; in the corresponding groups, 14% and 11% discontinued medications because of adverse events.