Serotonin (5-HT) receptors 2A are expressed in brain regions involved in memory and learning processes. Recently, a functional single nucleotide polymorphism in the 5-HT2A receptor gene leading to an amino-acid substitution at residue 452 (His452Tyr) has been involved in memory performance, persons with the rare 452Tyr allele showing poorer memory performance compared to His452His subjects. To investigate a putative structural effect of this polymorphism on temporal areas typically involved in memory processes, we performed voxel-based morphometry (VBM) and region-of-interest (ROI) volumetric analysis on high-resolution magnetic resonance images in 15 carriers and 61 noncarriers of the 452Tyr allele. ROI volumetric analysis showed a significant reduction of the fractional volume of the temporal white matter in 452Tyr carriers (0.67+/-0.07 vs 0.73+/-0.08; P=0.007). VBM confirmed this finding and in addition showed reduced grey matter in the left hippocampus, left inferior temporal gyrus, and bilaterally in the middle and superior temporal gyrus. A possible effect on synaptic plasticity or neurodevelopment might explain the influence of the His452Tyr polymorphism on temporal brain structures, and this might be the basis for poorer memory performance in 452Tyr carriers. These findings should be considered preliminary and future replication is needed.