Brain dopamine (DA) has been linked to error processing. Because high and low (vs medium) prefrontal cortex (PFC) DA levels may facilitate D2-receptor-related modulations of PFC neural activation patterns, we hypothesized that high and low DA predicts increased error-specific transitions of PFC activity. Male human participants (n= 169) were genotyped for thecatechol-O-methyltransferase (COMT) Val158Met polymorphism, associated with low (Val) and medium (Met) PFC DA levels. In addition,DRD2TaqIa and 5-HTTLPR, associated with striatal D₂receptor density and serotonin uptake, respectively, were assessed. Participants received placebo or a selective DA–D₂receptor blocker (sulpiride, 200 mg) and performed a Flanker task. EEG was recorded and decomposed into independent brain components (ICs) using independent component analysis. After errors, participants displayed (1) a negative deflection in ICs source-localized to the proximity of the anterior midcingulate cortex [IC-error-related negativity (IC-ERN)], (2) increased midcingulate cortex IC power in the delta/theta frequency range, and (3) slowing in the subsequent trial [posterror slowing (PES)]. Importantly, all, IC-ERN, delta/theta power, and PES were modulated byCOMT× Substance interactions such that the Val allele predicted elevated IC-ERN, delta/theta power, and PES after placebo; this association was reversed under sulpiride. Because low doses of sulpiride presumably increase PFC DA levels, theCOMT× Substance interaction supports the hypothesis that low (Val, placebo) and high (Met, sulpiride) versus medium (Val, sulpiride; Met, placebo) DA levels elevate reactivity to errors. Consistent with an influence of serotonin on PFC DA, theCOMT× Substance interaction was modulated by5-HTTLPR.