Abstract The Continuous Performance Task (CPT) is a widely-used measure of sustained attention and impulsivity. Deficits in CPT performance have been found in several psychiatric disorders, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and schizophrenia. Molecular genetic studies of CPT performance are currently limited and have generally revealed inconsistent findings. The current study tested the associations of the COMT val108/158met polymorphism with AX-CPT indices (i.e., omission and commission errors, d׳, and lnβ), as well as the variability of these indices across blocks, in a sample of clinic-referred and non-referred children (N=380). We found significant associations between COMT and variability in the Signal Detection Theory (SDT) indices d׳ and lnβ across blocks, as well as a statistical trend for association between COMT and commission errors. Higher externalizing psychopathology was associated with general impairment on AX-CPT performance, and for some indices (i.e., d׳ variability and lnβ variability) the effect of COMT was stronger at higher levels of psychopathology. Our findings support the role of COMT in components of CPT performance and highlight the potential utility of using SDT indices, particularly in relation to variability in performance. Moreover, our results suggest that for some indices the effect of COMT is stronger at higher levels of externalizing psychopathology. Our study yields some preliminary insights regarding the neurobiology of CPT performance, which may elucidate the mechanisms by which specific genes confer risk for various cognitive deficits, as well as relevant disorders characterized by these deficits.