This study examined, for the first time, whether a high CYP2D6-CYP2C19 metabolic capacity combination increases the likelihood of suicidal intent severity in a large study cohort. Survivors of a suicide attempt (n=587; 86.8% women) were genotyped for CYP2C19 (*2, *17) and CYP2D6 (*3, *4, *4xN, *5, *6, *10, wtxN) genetic variation and evaluated with the Beck Suicide Intent Scale (SIS). Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt (P<0.01) as measured by the SIS-objective circumstance subscale (odds ratio (OR)=1.37; 95% confidence interval (CI)=1.05-1.78; P=0.02) after adjusting for confounders (gender, age, level of studies, marital status, mental disorders, tobacco use, family history of suicide, personal history of attempts and violence of the attempt). Importantly, the risk was greater in those without a family history of suicide (OR=1.82; CI=1.19-2.77; P=0.002). Further research is warranted to evaluate whether the observed relationship is mediated by the role of CYP2D6 and CYP2C19 involvement in the endogenous physiology or drug metabolism or both.