OBJECTIVE: To evaluate the literature regarding the efficacy and safety of intravenous ketamine for treatment-resistant major depressive disorder (MDD). DATA SOURCES: A MEDLINE search (1966-September 2011) was performed using the terms treatment-resistant depression and ketamine. The search was restricted to articles published in English and reporting on use of ketamine in humans. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data search were evaluated. Data were eligible for inclusion if they were primary literature and evaluated the efficacy of ketamine for depressive symptoms in treatment-resistant MDD. One case report, 3 case series, 3 open-label trials, and 1 randomized crossover trial were included. DATA SYNTHESIS: Several medications are available for treatment-resistant MDD; however, they are often limited by a slow onset of therapeutic effect and tolerability. It has been suggested that ketamine, a rapid-acting, N-methyl-D-aspartate glutamate receptor antagonist, may have antidepressant effects. Case reports, case series, and select trials evaluating ketamine use for depressive symptoms in treatment-resistant MDD have demonstrated a rapid effect for reductions of scores on a number of depression scales; however, its sustainability effect remains unknown. Several studies reported a large or moderate to large effect size for ketamine. Additionally, these studies showed that ketamine use in this patient population is associated with relatively well-tolerated adverse effects. CONCLUSIONS: Ketamine for treatment-resistant MDD requires further evaluation before it can be considered a viable treatment option.