BACKGROUND This study employed an alternative method for assessing serotonergic function to further evaluate our finding that cerebrospinal fluid (CSF) 5-hydroxyindole acetic acid (5-HIAA) in depressed suicide attempters with a lifetime history of higher lethality suicide attempts is significantly lower compared to depressed patients who have a history of low lethality suicide attempts. METHODS We used dl-fenfluramine (60 mg) as a neuroendocrine probe to examine the serotonin system in 41 in-patients with a DSM-III-R major depressive episode, divided into two groups on the basis of a lifetime history of high or low lethality suicide attempts. Fenfluramine challenge test outcome was defined as the maximum prolactin response in the five hours following fenfluramine. RESULTS Patients with a history of a higher lethality suicide attempt had a significantly lower prolactin response to fenfluramine, even when controlling for cortisol, age, sex, weight, comorbid cluster B personality disorder, pharmacokinetic and menstrual cycle effects. CONCLUSIONS The data provide further support for the hypothesis that serotonin dysfunction is associated with more lethal suicide attempts, and suggests that higher lethality suicide attempters or failed suicides resemble completed suicides both behaviourally and biochemically.