© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society. Objectives To determine whether initiation of cholinesterase inhibitors is associated with significant weight loss in a real-word clinical setting. Design Retrospective cohort study from 2007 to 2010 comparing weight loss in individuals with dementia newly prescribed cholinesterase inhibitors and those newly prescribed other chronic medications. Setting National Veterans Affairs data. Participants Individuals aged 65 and older with a diagnosis of dementia who received a new prescription for a cholinesterase inhibitor or other new chronic medication. Measurements The primary outcome was time to 10-pound weight loss over 12 months. Propensity score matching was used to control for the likelihood of receiving a cholinesterase inhibitor based on baseline characteristics. Data were analyzed in a priori defined subgroups according to age, comorbid burden, and initial weight. Results Of 6,504 individuals that met study criteria, 1,188 started on cholinesterase inhibitors were matched to 2,189 started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Participants initiated on cholinesterase inhibitors had a higher risk of weight loss than matched controls at 12 months (hazard ratio = 1.23, 95% confidence interval (CI) = 1.07-1.41). At 12 months, 29.3% of participants taking cholinesterase inhibitors had experienced weight loss, compared with 22.8% of nonusers, corresponding to a number needed to harm of 21.2 (95% CI = 12.5-71.4) over 1 year. There were no significant differences in the risk of weight loss within subgroups. Conclusion These results are consistent with the available data from randomized controlled trials. Clinicians should consider the risk of weight loss when prescribing cholinesterase inhibitors.