Antidepressant medications are the most common psychopharmacologic therapy used to treat depressed nursing home (NH) residents. Despite a significant increase in the rate of antidepressant prescribing over the past several decades, little is known about the effectiveness of these agents in the NH population.To conduct a systematic review of the literature to examine and compare the effectiveness of antidepressant medications for treating major depressive symptoms in elderly NH residents.The following databases were searched with searches completed prior to January 2011 and no language restriction: MEDLINE, Embase, PsycINFO, CINHAL, CENTRAL, LILACS, ClinicalTrials.gov, International Standard Randomized Controlled Trial Number Register, and the WHO International Clinical Trial Registry Platform. Additional studies were identified from citations in evidence-based guidelines and reviews as well as book chapters on geriatric depression and pharmacotherapy from several clinical references. Studies were included if they described a clinical trial that assessed the effectiveness of any currently-marketed antidepressant for adults aged 65 years or older, who resided in the NH, and were diagnosed by DSM criteria and/or standardized validated screening instruments with Major Depressive Disorder, minor depression, dysthymic disorder, or Depression in Alzheimer's disease.A total of eleven studies, including four randomized and seven non-randomized open-label trials, met all inclusion and exclusion criteria. It was not feasible to conduct a meta-analysis because the studies were heterogeneous in terms of study design, operational definitions of depression, participant characteristics, pharmacologic interventions, and outcome measures. Of the four randomized trials, two had a control group and did not demonstrate a statistically-significant benefit for antidepressant pharmacotherapy over placebo. While six of the seven non-randomized studies identified a response to an antidepressant, their results must be interpreted with caution as they lacked a comparison group.The limited amount of evidence from randomized and non-randomized open-label trials suggests that depressed NH residents have a modest response to antidepressant medications. Further research using rigorous study designs are needed to examine the effectiveness and safety of antidepressants in depressed NH residents, and to determine the various facility, provider, and patient factors associated with response to treatment.