The catechol-O-methyltransferase (COMT) gene codes for the COMT enzyme, which has a role in the degradation of dopamine in the prefrontal cortex. The dopaminergic system declines with age, and aging might increase the effects of COMT on cognition. It is in particular the COMT Val158Met single nucleotide polymorphism (SNP) that has been investigated in association with cognition, but other COMT SNPs have also been studied. The ε4 allele of the Apolipoprotein E (APOE) gene is a known risk factor for Alzheimer’s disease, and APOE might also play an important role in normal cognitive aging. The present study investigates effects of COMT and APOE on executive function and age-related cognitive decline. Highly functioning participants (N = 670) in the age range 18–79 years had earlier been genotyped for COMT and APOE, and had completed several neuropsychological tests. This already existing dataset was analysed in the present study. It was hypothesized that the COMT Val158Met polymorphism would influence executive functioning, and that there would be interaction effects between COMT and APOE. A further prediction was that the effects of the genotype combinations would differ for young, middle-aged, and older participants. Effects of eight other COMT SNPs than the Val158Met SNP were also investigated. Significant interaction effects of COMT, APOE, and age were found, indicating that different allele combinations of COMT and APOE play a role in age-related cognitive decline.