OBJECTIVES: Inhaled anticholinergics are important pharmacologic interventions in the management of Chronic Obstructive Pulmonary Disease (COPD) with tiotropium bromide being the most prescribed COPD medication. Concerns regarding its association with cardiovascular adverse events have been raised. The objective of this study was to assess the risk of all-cause mortality associated with inhaled anticholinergics among COPD patients using systematic-review with meta-analysis techniques. METHODS: A systematic literature search was conducted using six electronic databases (PubMed, Scopus, Web-of-Science, Web-of Knowledge, Cochrane Central Register of Controlled Trials and Proquest) and cross-referencing. Studies meeting the following eligibility criteria were selected: 1) randomized controlled trials (RCTs) with mortality data; 2) adults aged greater >35 years with COPD of any severity; 3) inhaled anticholinergics (ipratropium bromide or tiotropium bromide) with a minimum follow-up of 4 weeks; and 4) placebo or active control group. Studies including asthma patients were excluded.  Data extraction was performed independently and relative risk (RR) estimates were calculated from each study. To determine the relationship between inhaled anticholinergics and mortality, data were pooled using the random effects model (inverse variance method). Between-study heterogeneity was assessed using the I2-statistic. RESULTS: Of the 684 citations reviewed, a total of 18 RCTs enrolling more than 33,000 patients met the inclusion criteria. Inhaled anticholinergics were not associated with an increased risk of all-cause mortality [RR=1.10 (95% CI: 0.88,1.36), I2=36%]. Tiotropium only group showed similar results. Subgroup analyses of soft mist inhaler (SMI) trials, however, revealed a 51% increase in all-cause mortality for the intervention group [RR=1.51; 95% CI (1.08,2.11), I2=0%]. Sensitivity analysis did not change any of the results. CONCLUSIONS: Overall, inhaled anticholinergics were not associated with an increased risk of all-cause mortality and might be considered as safe. Analyses of tiotropium-SMI subgroup, however, suggested an increase in mortality risk, necessitating more long term RCTs to assess its safety.