Recent studies suggest the presence of genetically distinct subtypes of attention deficit/hyperactivity disorder (ADHD) and that attention problems can be treated with receptor subtype selective nicotine agonists. In this study, individuals with two independent familial subtypes of ADHD defined by latent class analysis were systematically screened for sequence variations in the coding regions and intron/exon junctions of the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4). Common polymorphisms were used for transmission disequilibrium test (TDT) analyses. A significant association was found for a 5' intron 2 single nucleotide polymorphism and severe inattention problems (P = 0.007, effect size = 4, 95% CI 1.3-14.1). The location of the polymorphism is compatible with it affecting pre-mRNA stability or splicing.