A variation in catechol-O-methyltransferase (COMT) gene (Val(108/158)Met) affects the physiological response of hippocampal-prefrontal circuits, predicts variation in human memory and is associated with increased risk for psychiatric disorders. Using optimized voxel-based morphometry we studied the effect of this functional polymorphism on the anatomy of the hippocampus, and the prefrontal cortex. Fifty-seven healthy participants were investigated (nine had Met/Met, 30 Val/Met, and 14 Val/Val). Voxel-based morphometry showed that individuals who are homozygous for the Val-COMT allele had greater gray matter volume of the prefrontal cortex bilaterally, whereas Met-COMT carriers were associated with increased tissue volume of the hippocampus bilaterally. This study provides evidence that the Val(108/158)Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.