Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. Recent human studies have indicated that a common single nucleotide polymorphism of the BDNF gene, the Val66Met polymorphism, has impact on episodic memory, hippocampal morphology and memory-related hippocampal activity measured by functional magnetic resonance imaging (fMRI). However, two issues remain to be clarified: (1) whether the genotype effect of this polymorphism on memory-related brain activity is allele dose dependent and (2) whether the effect of this polymorphism in Asian population is the same as effects observed in Caucasian sample. To clarify these issues, we studied the relationship of the Val66Met polymorphism genotype and hippocampal activity during episodic memory task using fMRI in healthy 58 biologically unrelated Japanese. Although there was no genotype effect on episodic memory function obtained by behavioral assessments, fMRI measurements revealed a significantly negative correlation between the dose of Met-BDNF allele and encoding related brain activity in the bilateral hippocampi and right parahippocampal gyrus. There was no genotype effect on retrieval related brain activity. These data indicated a genetic mechanism for normal variation in human memory and suggest effects of BDNF signaling on hippocampal function in humans.