OBJECTIVES Recent questions have been raised about ipratropium safety in chronic obstructive pulmonary disease (COPD). However, these studies have failed to examine potential benefits of ipratropium. Our objective was to evaluate the comparative effectiveness of ipratropium versus other COPD medications. METHODS We conducted a cohort study in veterans diagnosed with COPD between October 2002 and September 2003. Patients were followed up to 2.5 years for all-cause mortality, COPD exacerbations and COPD-related hospitalizations. Time-varying medication exposure was determined for inhaled corticosteroids (ICS), ipratropium (IPRA), long-acting beta-agonists (LABA), and theophylline (THEO) during follow-up. Risk indices were used to divide the cohort into low, moderate and high risk groups. Cox proportional hazards regressions were used to examine associations between medication regimen exposure and events, stratified by risk index and adjusted for propensity to use ipratropium. RESULTS From 108,426 patients, there were 16,539 deaths, 42,109 with an exacerbation and 14,828 with a COPD-related hospitalization. Compared with LABA, there was a significant increase in the mortality risk associated with IPRA in the moderate (HR=1.54 [95% CI 1.19-2.01] and high risk (HR=1.30 ([1.09-1.55]) groups. For exacerbations, IPRA was associated with an increased risk in the low risk group (HR=1.64 [1.40-1.92]), but not in either the moderate (HR=0.97 [0.85-1.09]) or high risk group (HR=0.94 [0.84-1.05]). CONCLUSIONS We found an increased risk of mortality associated with ipratropium that varied by baseline risk of event. The findings elevate concerns about potential harms associated with ipratropium in COPD that do not appear to be offset by reduction in COPD events.