The analgesic tramadol has many characteristics in common with the antidepressant venlafaxine. The drugs are structurally similar, share both serotonergic and noradrenergic properties, and undergo a similar metabolic fate. In this study, a patient, who developed significant depression following cessation of tramadol after several years of therapy, is described. Her depression was then treated with venlafaxine with excellent response. It appears that tramadol may have provided a prophylactic antidepressant effect in this patient. Because of its similarities to venlafaxine, tramadol may possibly exert a degree of antidepressant effect in certain patients, particularly those with chronic pain.