OBJECTIVES: Brain-derived neurotrophic factor (BDNF) is involved in major depressive disorder and neurodegenerative diseases. Clinical studies, showing decreased serum BDNF levels, are difficult to interpret due to limited knowledge of potential confounders and mixed results for age and sex effects. We explored potential determinants of serum BDNF levels in a community sample of 1230 subjects. METHODS: Multiple linear regression analyses with serum BDNF level as the dependent variable were conducted to explore the effect of four categories of potential BDNF determinants (sampling characteristics, sociodemographic variables, lifestyle factors and somatic diseases) and of self-reported depressive symptoms (Beck's Depression Inventory (BDI). RESULTS: Our results show that BDNF levels decline with age in women, whereas in men levels remain stable. Moreover, after controlling for age and gender, the assays still showed lower serum BDNF levels with higher BDI sum scores. Effects remained significant after correction for two main confounders (time of sampling and smoking), suggesting that they serve as molecular trait factors independent of lifestyle factors. CONCLUSIONS: Given the age-sex interaction on serum BDNF levels and the known association between BDNF and gonadal hormones, research is warranted to delineate the effects of the latter interaction on the risk of psychiatric and neurodegenerative diseases.