There are several reported associations between depressive disorders, panic disorder, and obsessive–compulsive disorder (OCD) and a variety of polymorphisms in the monoamine oxidase A (MAOA) gene. Associations have also been reported between the catechol-O-methyltransferase (COMT) gene and both OCD and bipolar depression. However, the role of these markers has not been explored for the personality trait of neuroticism (N), a normally distributed quantitative trait, which is highly genetically correlated with anxiety and depression and may be a vulnerability to either type of disorder. We explored the possible role of MAOA, COMT, and their interaction on N using a selected extremes design. From a sample of 2,085 individuals, each assessed for N by two independent peers rather than using self-report questionnaires, we selected 57 individuals from the top 10% of scores, and 62 individuals from the bottom 10%. Using selected extreme low subjects as the controls, rather than an unselected control group gives roughly twice the power of a standard case-control design. We typed a functional variable number tandem repeat (VNTR) in the MAOA gene promoter, and a functional polymorphism in the coding region of the COMT gene. Two novel alleles in the MAOA VNTR were identified on the basis of their size, and their structure examined by sequencing analysis. We found weak evidence for association with COMT genotype, when the females and males were considered separately, and for MAOA genotype in males only. There was no significant interaction between COMT and MAOA. © 2003 Wiley-Liss, Inc.