Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. In the current investigation, a catechol-O-methyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. Using a haplotype relative risk design and a parent-to-proband allele transmission test with 48 ADHD triads, we found an association between COMT and illness ( 2 = 4.72, p = 0.03, df = 1). In particular, the impulsivehyperactive type of ADHD (excluding inattention) ascertained by Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria ( 2 = 8.34, p = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pearson 2 = 5.32, p = 0.02, df = 1) as well as by the Continuous Performance Test False Alarm scale ( 2 = 2.78, p = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtained if genotype frequencies were compared. It should be noted that the association between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methylphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:497-502, 1999.