Although acute hepatitis may be a side effect of many medications, most cases are reversible after treatment interruption, and fulminant hepatic failure (FHF) is rare. Venlafaxine and trazodone are 2 popular antidepressant agents. Alteration of liver enzyme levels has been reported as a side effect of these drugs at normal doses. Herein we have reported the case of a 48-year-old woman without any previous history of liver disease, who developed fulminant liver failure after 4 months of venlafaxine and trazodone therapy. She required liver transplantation, a procedure that was successful with full patient recovery. The first 5 years of follow-up were uneventful. This case documented that venlafaxine and trazodone at normal doses can produce severe liver toxicity. Liver tests should be monitored regularly in patients who receive this therapy.