The clinical trial of tiotropium in chronic obstructive pulmonary disease (COPD), i.e. UPLIFT, enrolled adults with a mean age of 65 years and moderate-to-severe airflow-obstruction, based on criteria from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). For the UPLIFT cohort, however, GOLD-based criteria are not age-appropriate.Will the use of more age-appropriate criteria for airflow-obstruction from the Global Lung Function Initiative (GLI) modify the spirometric classification of the UPLIFT cohort and, in turn, the mortality effect of tiotropium in COPD?and Methods: Baseline spirometric classifications were first cross-tabulated by GLI- and GOLD-based criteria. Next, in GLI- and GOLD-based airflow-obstruction, modified intention-to-treat analyses evaluated differences in time-to-death over 4 years, comparing tiotropium vs. placebo. Since treatment response may differ by COPD severity, the mortality effect was also evaluated within stratum defined by GLI- and GOLD-based moderate and severe airflow-obstruction.Of 5898 participants with GOLD-based airflow-obstruction, staged as moderate in 2739 (46.4%) and severe in 3156 (53.5%), GLI-based criteria established airflow-obstruction in 5750 (97.5%), staged as moderate in 795 (13.5%) and severe in 4947 (83.9%). Relative to placebo, tiotropium yielded statistically non-significant adjusted hazard ratios (adjHRs) (95% confidence interval) for death of 0.91 (0.80, 1.04) and 0.91 (0.79, 1.03) in GLI- and GOLD-based airflow-obstruction, respectively. However, statistically significant effect modification was observed, but only in GLI-based moderate and severe airflow-obstruction, with tiotropium yielding adjHRs for death of 0.53 (0.34, 0.81) and 0.99 (0.86, 1.13), respectively-P value for interaction was 0.007.Mortality reduction by tiotropium was only statistically significant in GLI-based moderate airflow-obstruction, a group which was under-represented in UPLIFT due to severity misclassification by the original GOLD-based enrollment criteria.