Previous studies have found that not all suicide attempters with major depression have reduced serotonergic activity based on low cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF- 5-HIAA) levels. In this study we hypothesized that serotonergic function is lower in depressed patients who have carried out high-lethality suicide attempts resulting in more medical damage, which might explain differences in serotonergic activity among depressed suicide attempters. We assessed the relationship of CSF 5-HIAA and other amine metabolites to the most lethal lifetime suicide attempt in 22 drug-free inpatients with major depression. CSF 5-HIAA levels were lower in depressed patients with a history of a high-lethality or well-planned suicide attempt compared to depressed patients with a history of only low-lethality suicide attempt(s). Other CSF monoamine metabolites did not correlate with suicidal behavior. Low serotonergic activity may correlate with a predisposition to more lethal suicide attempts in major depression.