OBJECTIVES: For persons with dementia, the appropriate duration of cholinesterase inhibitor (ChEI) use remains unclear. We examined patterns of ChEI use during nursing home (NH) transition and the factors associated with discontinuation following admission. DESIGN: Population-based retrospective cohort study using linked health administrative and Resident Assessment Instrument Minimum Dataset, version 2.0 databases. SETTING AND PARTICIPANTS: A total of 47,851 older adults (mean age = 84.8 years, standard deviation = 6.8) with dementia newly admitted to a NH in Ontario, Canada between 2011 and 2015. MEASUREMENTS: ChEI use at admission and during the following year was identified from prescription claims. Resident sociodemographic and health characteristics at admission, including a 72-item frailty index, were derived from the Resident Assessment Instrument Minimum Dataset 2.0. Additional resident and prescriber characteristics were derived from administrative data. Discontinuation was defined as a 30+-day gap in ChEI supply. Multivariable subdistribution hazard models were used to estimate the independent effect of resident frailty and other factors on ChEI discontinuation. RESULTS: Approximately one-third (17,560) of residents with dementia were on a ChEI at admission. Among this group, 17.7% (3110) discontinued use over follow-up. Incidence of discontinuation was significantly higher among residents with syncope [subdistribution hazard ratio, sHR = 2.21, 95% confidence interval, CI (1.52, 3.22)], more severe behavioral symptoms [sHR = 1.79, 95% CI (1.57, 2.05)], cognitive impairment [sHR = 1.26, 95% CI (1.07, 1.48)], higher frailty, [sHR = 1.19, 95% CI (1.04, 1.36)], and a primary prescriber active in the NH [sHR = 1.28, 95% CI (1.14, 1.45)]. A significantly lower incidence was observed for older and unmarried residents and those with a longer duration of use. CONCLUSIONS/IMPLICATIONS: Less than one-fifth of residents on a ChEI at admission discontinued use during the following year. Although some of the predictors of discontinuation align with past research and current clinical recommendations, others were unexpected and point to novel drivers of ChEI use. Future investigations should explore the varied reasons underlying these associations and resident outcomes associated with ChEI discontinuation.