Attention deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder that presents in childhood and that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD: (a) nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers and non-smokers; (b) ADHD is a significant risk factor for early initiation of cigarette smoking in children; (c) maternal cigarette smoking appears to be a risk factor for ADHD; (d) animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity; and (e) a central nicotinic agonist, ABT-418, improves attention in both monkeys and ADHD adults. The current study examined the alpha 4 receptor, one of the sites of action of ABT-418. A known Cfol polymorphism within the nicotinic acetylcholine alpha 4 receptor gene, CHRNA4, was studied in 70 ADHD parent-proband trios from an ongoing sample collection of children aged 6-12 with ADHD, according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. The Transmission Disequilibrium Test demonstrated no evidence that variation at the nicotinic acetylcholine alpha 4 receptor Cfol polymorphism influences susceptibility to ADHD (P > 0.35). The continuing sample collection will enable further study of other potential nicotinic system polymorphisms in ADHD in more powerful samples.