AbstractGenetic variation within the dopamine D4 receptor (DRD4) gene has been implicated in many neuropsychiatric disorders and behavioral traits. This variation includes the extensively studied exon 3 variably numbered tandem repeat (VNTR), and several 5′ polymorphisms including a120‐bp duplication and two single‐nucleotide polymorphisms at −521 C/T (rs1800955) and −616 C/G (rs747302). Several reports have provided evidence for a functional role for some of these variants using in vitro techniques. This study investigated the functionality of these polymorphisms in 28 human post‐mortem brain tissue samples by quantifying DRD4 mRNA expression in relation to genotype. No statistically significant relationship between genotype and mRNA expression levels was found for these four polymorphisms although a weak trend toward the 7‐repeat of the exon 3 VNTR reducing DRD4 mRNA expression was found. Employing post‐mortem brain tissue, rather than using in vitro techniques may provide a more relevant paradigm to study functional effects of reported risk alleles. © 2010 Wiley‐Liss, Inc.