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Randomized controlled trials at times investigate findings suggested by observational studies. For example, the Towards a Revolution in COPD Health (TORCH) trial, which did not show a mortality reduction with inhaled corticosteroids (ICS) in COPD, was motivated by some observational studies that suggested considerable reductions in mortality with these drugs. Reasons for these discrepancies are unclear.The literature was searched to identify all observational studies, including cohort and case-control studies, investigating the effectiveness of ICS on major outcomes in patients with COPD; these outcomes included death and hospitalization for COPD.A total of 21 studies were identified. Nine studies were affected by immortal time bias, five by immeasurable time bias, and seven by the “asthma factor” bias; some studies were affected by more than one bias. These studies found important reductions in the rates of major COPD outcomes with ICS use, with pooled rate ratios of 0.71 (95% CI, 0.67-0.76), 0.76 (95% CI, 0.70-0.83), and 0.79 (95% CI, 0.73-0.87), respectively, for the three sources of bias. In contrast, the five studies unaffected by these major biases did not find an association (pooled rate ratio, 1.02 [95% CI, 0.88-1.17]).Observational studies are important to provide evidence from real-world data on medication effects. However, appropriate study design and analysis are essential to avoid biases and ensure randomized trials with greater chances of success. The observational studies suggesting potential beneficial effects of nonrespiratory drugs to treat COPD, such as statins and beta-blockers, will also need careful review before long and expensive randomized trials are conducted.