The relation of the Catechol-O-Methyltransferase Val108/158Met (COMT, rs4680) and Brain-Derived Neurotrophic Factor BDNF Val66Met (BDNF, rs6265) polymorphisms with dopamine neurocircuitry and brain functions make them strong candidates for investigating the association between genes and cognitive function. Further, both of these polymorphisms have been implicated in risk for psychotic disorders, as well as cognitive impairment in psychosis. Nonetheless, findings on the association of these genes with cognition are mixed. Although the cumulative findings provide no consistent evidence to support an association of COMT or BDNF with vulnerability to psychosis, or of COMT with cognition, recent studies suggest an interactive effect of COMT and BDNF on cognitive performance. Based on these findings, the present study examined both the main and interactive effects of COMT and BDNF on cognition in schizophrenia-spectrum patients (patients diagnosed with psychosis or schizotypal personality disorder) and controls. The Logical Memory I and II and Letter-number Sequence subtests of the Wechsler Memory Scale, 3^rd Edition (WMS-III) were administered. There was no main or interactive effect of the two polymorphisms on cognition within the schizophrenia-spectrum sample. Exploratory analyses revealed significant sex-specific effects; however, these were based on small subsamples, and should be interpreted with caution. Limitations of the present study, most notably the low frequency of BDNF Met carriers, constrained statistical power for detecting effects. The present findings highlight the complex nature of genetic effects on cognition.