Clostridium difficile (C.difficile) infection (CDI) is a common and clinically significant cause of diarrhea associated with the use of antibiotic drugs. Two observational studies have suggested that antidepressant drug use is associated with an increased risk of developing CDI. Because of the potential public health significance of this finding, this article critically evaluates the methodology of these studies and provides evidence to question the plausibility and validity of this finding. The safety of antidepressant and other psychotropic drugs should not be taken for granted, but studies that receive media attention may cause harm if their findings are not valid and they result in a reluctance to use these drugs for treating serious mental disorders.