Catechol-O-methyltransferase (COMT) and dopamine receptors 2 (DRD2) and 3 (DRD3) have been associated with a higher risk of developing psychosis and with dopaminergic system (DAS) regulation. Frontal cognitive functioning has been proven to be a useful endophenotype for psychosis and it is partially controlled by the DAS. Val158Met (rs4680, COMT), Taq IA (rs1800497, DRD2) and Ser9Gly (rs6280; DRD3) polymorphisms were analyzed in a sample of 84 adolescent Caucasian patients with first-episode psychosis (ages 11–17) and 85 healthy Caucasian controls (ages 10–17). A comprehensive neuropsychological battery, assessing attention, working memory, memory, and executive functions, was administered to the entire sample. The relationship between neuropsychological scores and genotype was determined. Subjects with the DRD3 Gly/Gly genotype showed significantly poorer performance than Ser/Ser subjects in executive functioning tasks (P = 0.002; adjusted R2 = 0.031), with no significant differences in the other cognitive paradigms. Neither COMT nor DRD2 polymorphisms significantly contributed to variance in cognition in our adolescent sample. The DRD3 Ser9Gly polymorphism seems to be involved with prefrontal cognition. This effect seems to be heterogeneous in terms of cognitive paradigms. The lack of association between COMT and DRD2 genotypes and cognition in our sample may be partially explained by the young age of the sample and the clinical heterogeneity of the patients. © 2008 Wiley-Liss, Inc.