Recent reports have described neurobehavioral impairments in human subjects carrying a V66M polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF). Inasmuch as ventral nervous system (CNS) deficits associated with this BDNF polymorphism are similar to those observed among subjects with chronic exposure to elemental mercury (Hg degrees ), we examined the potential effect of this BDNF polymorphism on symptoms and mood in an established cohort of dental practitioners with chronic low-level Hg degrees exposure. Self-reported symptoms and mood were obtained by computerized questionnaire from 193 male dentists (DTs) and 230 female dental assistants (DAs). Spot urine samples were analyzed for mercury concentrations to evaluate recent exposure. Detailed work histories were obtained to calculate chronic indices of Hg degrees exposure. Buccal cell samples were obtained to identify the V66M polymorphism of BDNF. Scores for 11 current and 12 recent and chronic symptom groups, along with six mood factors, were evaluated with respect to recent and chronic Hg degrees exposure and BDNF polymorphism. Multiple regression analysis controlled for age, race, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Separate evaluations were conducted for DTs and DAs. Twenty-three associations between recent or chronic Hg degrees exposure and BDNF status and self-reported symptoms were observed with p < 0.10. All but three were in the expected direction (symptom scores increasing with Hg degrees exposure or BDNF polymorphism), and all but six were among DAs. All eight correlations between chronic exposure indices and recent and chronic symptoms among DAs were in the expected direction. All seven associations between BDNF and symptoms were in the expected direction and split between DTs and DAs. All three associations with mood factors were among DAs and in the expected direction. These results indicate that among DAs very low levels of occupational Hg degrees exposure are associated with increased symptoms. The BDNF polymorphism is also associated with increased symptom and mood scores. Notably, Hg degrees and BDNF polymorphism were additive with respect to their associations with the same symptom group.