Anxiety is known to be influenced by both adverse childhood experiences and genetic susceptibility factors. A polymorphism in the brain-derived neurotrophic factor (BDNF) gene modulates the association between adverse early experiences and risk for anxiety and depression in adulthood. An animal model of this gene-by-environment risk factor is lacking. Using two different early environmental manipulations, we found that a heterozygous null mutation in the mouse BDNF gene moderated the long-term effect of maternal care on innate anxiety behavior. Although changes in maternal care were associated with mild changes in anxiety in wild-type mice, this effect was magnified in heterozygous null BDNF mice with high- and low-maternal care associated with low and high levels, respectively, of avoidance behavior as measured in the open field and elevated plus maze tests. These data argue for an increased sensitivity to early environmental influences of mice with reduced BDNF function and support the important role of this neurotrophic factor in the developmental plasticity of brain circuits controlling anxiety.