Background: In the 4 year UPLIFT trial, tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with COPD. Mortality and its causes was a secondary endpoint in UPLIFT. In this report we describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow up of discontinued patients. Methods: Randomized, double-blind trial comparing tiotropium with placebo in COPD patients age 40 years, post-bronchodilator FEV₁70%, FEV₁/FVC70%. Mortality was evaluated during treatment and with follow-up of discontinued patients. Cause of death was adjudicated by an endpoint committee. Results: 5,993 patients were randomized, 3,006 to placebo and 2,987 to tiotropium. While receiving treatment, there were 792 deaths, with a lower risk in the tiotropium group (hazard ratio (HR) (95%CI) = 0.84 (0.73, 0.97). Statistical significance was observed at the end of the protocol defined treatment period (p=0.034), but not 30 days thereafter (p=0.086). Adjustment by GOLD stage, gender, age, baseline smoking behavior and baseline respiratory medications subgroups did not alter the results of the analysis. The most common causes of death adjudicated by an independent end-point committee were: lower respiratory, cancer, general disorders and cardiac. The HR (95%CI) for lower respiratory and cardiac mortality during treatment were 0.86 (0.68, 1.09) and 0.86 (0.75, 0.99) respectively. Conclusion: Treatment with tiotropium over 4 years is associated with decreased mortality, with the effect being most prominent in the cardiac and respiratory systems. Clinical Trial Registry Information: ID# NCT00144339 registered at www.clinicaltrials.gov