OBJECTIVES: Anticholinergic medications are commonly prescribed in elderly for the management of several geriatric problems. However, these medications are often associated with non-selective central and peripheral effects. The aim of the current study was to examine the risk of mortality associated with anticholinergic medication use among elderly nursing home residents with depression. METHODS: The study employed a population-based nested case-control design using 2007-2010 Minimum Data Set (MDS)-linked Medicare data from all statesThe base cohort included Medicare beneficiaries aged > 65 years, diagnosed with depression as of 2007, and any MDS assessment in 2007 (Base Period). Cases were identified as patients who died anytime between January 1, 2008 and December 31, 2010. For each case, 4 age- and sex-matched controls were selected using incidence density sampling. Anticholinergic exposure was defined using Anticholinergic Drug Scale (ADS). Prescription of clinically significant anticholinergic medications (level 2/3) 60 days preceding the event date formed the primary exposure. Conditional logistic regression model stratified on matched case-control sets was performed to assess mortality risk, after controlling for other risk factors of the outcome. RESULTS: The study sample included 44,948 cases with death and 179,792 matched controls. After adjusting for other risk factors, clinically significant anticholinergic use was associated with 31% increased risk of death (Odds Ratio, OR: 1.31; 95% CI: 1.28-1.34) compared to non-use. The findings varied across levels of anticholinergic potency (level 2, OR: 1.02, 95% CI: 0.98-1.06; level 3, OR: 1.46, 95% CI: 1.42-1.51). CONCLUSIONS: Use of clinically significant anticholinergic medications was associated with 31% increase in risk of mortality among elderly nursing home residents with depression. With increasing safety concerns, there is a significant need to optimize anticholinergic use in the vulnerable geriatric population.