OBJECTIVE: The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis. METHOD: Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz syndrome and 54 matched comparison subjects. RESULTS: There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz syndrome carriers than among the comparison subjects. CONCLUSIONS: These results, based on a unique study design, provide additional evidence supporting the relationship between cholesterol metabolism and suicidal behavior.