OBJECTIVE: The catechol O-methyltransferase (COMT) gene affects how long dopamine acts in the prefrontal cortex. The Methionine polymorphism, which results in a slower breakdown of prefrontal dopamine, is associated with better adult prefrontal cortex function. The authors investigated the relation between the COMT gene polymorphism and cognitive performance in children. METHOD: Children were tested on cognitive tasks that depend on the dorsolateral prefrontal cortex and seem to be sensitive to the level of dopamine there (dots-mixed task), depend on that neural region but appear insensitive to its dopamine content (self-ordered pointing), and depend on other neural systems (recall memory and mental rotation). After data collection, cheek swabs were obtained from all children. DNA was extracted and genotyped for the COMT gene with polymerase chain reaction. RESULTS: Children who were homozygous for the Methionine polymorphism performed significantly better on the dots-mixed task but not on others. CONCLUSIONS: The findings provide an existence proof that genotypic differences can relate to differences in cognitive performance in typically developing children. The authors achieved a level of specificity never previously attempted; the COMT polymorphism was found to be differentially related to performance on tasks linked to the same prefrontal region by whether cognitive requirements of the tasks were sensitive to the level of dopamine found. These results challenge accepted notions that since dopamine is important for some cognitive functions dependent on the prefrontal cortex, it is important for all. The differential sensitivity of distinct cognitive abilities to specific neurotransmitters may make possible targeted pharmacological interventions.