Genetic factors influence vulnerability to depression (Sullivan et al, 2000), but no specific genes have been definitively implicated. One promising approach is to determine whether variations in specific (candidate) genes are associated not with disease per se, but with traits, such as personality factors, that are themselves associated with risk for the disorder (Lander and Schork, 1994; Stoltenberg and Burmeister, 2000). Often such traits have a higher heritability than the disease status (Almasy and Blangero, 2001). Neuroticism, as measured by the NEO personality inventory (NEO-PI) (Costa and McCrae, 1997), a psychometrically sound and widely used instrument, is one such trait. High scorers on the Neuroticism domain are characterized by frequent experience of “negative emotionality” such as anxiety, low mood, and hostility. Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. To explore the possibility that variation in the BDNF gene is, in part, responsible for the population variation in Neuroticism, we studied a community sample of 441 subjects, genotyping a G→A single-nucleotide polymorphism (SNP) responsible for a valine→methionine substitution in the prodomain of BDNF. The less common, nonconserved Met allele was associated with significantly lower mean Neuroticism scores (p = 0.0057). Our study provides further evidence and one possible mechanism linking BDNF to depression.