CONTEXT Atypical antipsychotic medications are commonly used for off-label conditions such as agitation in dementia, anxiety, and obsessive-compulsive disorder. OBJECTIVE To perform a systematic review on the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration. DATA SOURCES AND STUDY SELECTION Relevant studies published in the English language were identified by searches of 6 databases (PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL) from inception through May 2011. Controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included. Observational studies with sample sizes of greater than 1000 patients were included to assess adverse events. DATA EXTRACTION Independent article review and study quality assessment by 2 investigators. DATA SYNTHESIS Of 12 228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm NNH = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms. CONCLUSIONS Benefits and harms vary among atypical antipsychotic medications for off-label use. For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common.