The Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT) trial was a global 4-year randomized placebo-controlled clinical trial that evaluated the long-term impact of tiotropium bromide 18 microg once daily on the accelerated age-related decline in pre- and post-bronchodilator forced expiratory volume in 1 s (FEV(1); co-primary end points). Secondary end points included lung function at serial clinic visits, health-related quality of life, exacerbations, exacerbation-related hospitalizations, mortality, safety and tolerability. The study was carried out in 5992 patients (75% male, mean age 65 years, 30% current smokers) with moderate-to-very severe chronic obstructive pulmonary disease who were permitted to receive prescribed treatment with long-acting beta(2)-agonists and/or inhaled corticosteroids in addition to the study drug. While the results failed to show an effect of tiotropium on the primary end points (rate of decline in pre- and post-bronchodilator FEV(1)), they did show improvements in lung function and health-related quality of life that were maintained throughout the study and a reduction in the risk of exacerbations and related hospitalizations. Tiotropium also reduced all-cause mortality in patients on treatment over the 4-year trial period and reduced lower respiratory and cardiovascular morbidity, including respiratory failure and myocardial infarction. Adverse events were consistent with the drug's known anticholinergic pharmacology.