OBJECTIVES:  Recent studies have indicated an increased risk of cardiovascular diseases (CVDs) from tiotropium, a long-acting muscarinic antagonist, and long-acting beta-agonists (LABAs). Given tiotropium is commonly added to LABAs in combined with inhaled corticosteroids (ICSs) in chronic obstructive pulmonary disease (COPD), we examined whether add-on of tiotropium is associated with an increased CVD risk in a COPD population. METHODS:  This nested-case control study consisted data of 68,456 COPD patients aged ≥ 40 years and continuously treated with ICSs and LABAs, retrieved from the Taiwan National Health Insurance Research Database during 2007-2011. Cases were patients who had a hospitalization or emergency room visit with a primary diagnosis of ischemic heart disease, heart failure, ischemic stroke, or arrhythmia during follow-up. Using risk set sampling, controls were randomly selected at a 1:4 ratio matched for age, sex, cohort entry, prior CVD type, tiotropium, ICS/LABA use at baseline, asthma and COPD exacerbation preceding an index date. Conditional logistic regressions were employed to estimate odds ratios (ORs) for the CVD risk from add-on of tiotropium, with adjustment of confounders. RESULTS:  There were 3,966 CVD cases and 11,273 controls. Newly initiation of tiotropium was associated with a 1.59-fold (95% confidence interval, 1.35-1.87) increased CVD risk, whereas the risk was absent with current continuous, recent, and past use. A 1.97-fold (1.57-2.47) increased risk was observed for new use of one canister of tiotropium, but decreasing and disappearing with 2 (adjusted OR 1.50; 95% CI, 1.14-1.98) and ≥ 3 canisters (1.09; 0.77-1.52), respectively. Similarly, the highest risk (2.36; 1.71-3.25) was present with tiotropium therapy for 1-14 days; the risk was attenuated with 15-28 days (1.79; 1.41-2.26) and absent for > 28 days (1.03; 0.78-1.36). CONCLUSIONS:  In COPD patients on ICS and LABA therapy, new tiotropium use was associated with an increased CVD risk, especially when the therapy is implemented within 14 days.