OBJECTIVES To date, there is mixed evidence on the safety and effectiveness of tiotropium. Our objective was to evaluate the comparative effectiveness of regimens containing tiotropium versus other medication regimens for chronic obstructive pulmonary disease (COPD) in real-world clinical settings. METHODS We conducted a cohort study on two separate cohorts with a diagnosis of COPD in the VA health care system. Patients with a COPD diagnosis prescribed tiotropium and patients in a historic cohort prior to the introduction of tiotropium were selected for comparison using propensity scores, with the base case including scores from 0.1 to 0.4. Outcomes identified during follow-up were all-cause mortality, COPD exacerbations, and COPD hospitalizations. Exposure to COPD medication regimens was defined in a time-varying manner and Cox proportional hazards regression were employed to evaluate outcomes. RESULTS For 42,090 patients in the base case, the regimen of tiotropium plus inhaled corticosteroids plus long-acting beta-agonists was associated with 40% reduced risk of death (HR=0.60 [95% CI 0.45, 0.79]) compared to inhaled corticosteroids plus long-acting beta-agonists. This combination was also associated with reduced rates of COPD exacerbations (HR=0.84 [0.73, 0.97]) and COPD hospitalizations (HR=0.78 [0.62, 0.98]). Tiotropium in combination with other medication regimens was associated with increased risk of events compared to inhaled corticosteroids plus long-acting beta-agonists. CONCLUSIONS When used with inhaled corticosteroids and long-acting beta-agonists, tiotropium use was associated with a decreased risk of mortality compared to treatment with inhaled corticosteroids and long-acting beta-agonists. However, this result was not consistent in other medication regimens that included tiotropium.