The study aimed to investigate the association of acetylcholinesterase inhibitors (AChEIs) use with the risk of acute coronary syndrome (ACS). We conducted a population-based retrospective cohort study of dementia patients during 1 January 1999 to 31 December 2008 using the National Health Insurance Database in Taiwan. New AChEI users during the study period were matched with AChEI nonusers in age-matched and gender-matched cohorts. The risk of ACS associated with use of AChEIs was analyzed using modified Kaplan-Meier analysis and Cox proportional hazard models after adjustment for competing death risk. Use of AChEIs was associated with a lower incidence of ACS (212.8/10,000 person-years) compared to the matched reference cohort (268.7/10,000 person-years). The adjusted hazard ratio for ACS in patients with dementia treated with AChEIs was 0.836 (95% confidence interval, 0.750-0.933; P < 0.001). Further sensitivity analysis of different study populations demonstrated consistent results. A statistical dose-response relationship for AChEI use and ACS risk was significant for the patients with dementia. In patients with dementia, AChEI treatment was associated with decreased risk of ACS.