It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930–1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies. © 2008 Wiley-Liss, Inc.