Hoarding disorder, classified as a separate disorder in Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), is a common, chronic, and potentially disabling syndrome that can be difficult to treat. Only one previous study prospectively measured response to pharmacotherapy in compulsive hoarders, finding that hoarders responded as well to paroxetine as did nonhoarding obsessive-compulsive disorder patients. However, paroxetine was not tolerated well in that study, and the overall response was moderate. Therefore, we conducted an open-label trial of venlafaxine extended-release for hoarding disorder. Twenty-four patients fulfilling the DSM-5 criteria for hoarding disorder were treated with venlafaxine extended-release for 12 weeks. All patients were free of psychotropic medications for at least 6 weeks before the study. No other psychotropic medications, cognitive-behavioral therapy, organizers, or cleaning crews were permitted during the study. To measure the severity of hoarding, the Saving Inventory-Revised (SI-R) and the UCLA Hoarding Severity Scale (UHSS) were administered before and after treatment. Twenty-three of the 24 patients completed treatment. Hoarding symptoms improved significantly, with a mean 36% decrease in UHSS scores and a mean 32% decrease in SI-R scores. Sixteen of the 23 completers (70%) were classified as responders to venlafaxine extended-release. These results suggest that venlafaxine extended-release may be effective for the treatment of hoarding disorder.