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A variation in catechol-O-methyltransferase (COMT) gene (Val108/158Met) 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 Val108/158Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.