The causal role of sertraline in rare cases of liver failure in patients taking the drug has not been proven in a manner consistent with usually accepted standards. We describe an individual who developed clinically significant hepatitis while being treated with sertraline. This case is significant because it is the only one of which we are aware in which the diagnosis of sertraline hepatotoxicity was confirmed when inadvertent rechallenge with the medication resulted in recurrent hepatitis. We review this case and the general role of this widely prescribed class of drugs in causing hepatitis.