Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol- O -methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n -back task, we used signal detection theory to measure performance in a healthy adult population ( n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d ′ measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT × DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMT ValVal individuals, but impaired target detection in COMT Met carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT ValVal ) but impairs target detection in those with putatively higher frontal DA levels (COMT Met carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory.