Fluid intelligence (gf) influences performance across many cognitive domains. It is affected by both genetic and environmental factors. Tasks tapping gf activate a network of brain regions including the lateral prefrontal cortex (LPFC), the presupplementary motor area/anterior cingulate cortex (pre-SMA/ACC), and the intraparietal sulcus (IPS). In line with the “intermediate phenotype” approach, we assessed effects of a polymorphism (val158met) in the catechol-O-methyltransferase (COMT) gene on activity within this network and on actual task performance during spatial and verbal gf tasks. COMT regulates catecholaminergic signaling in prefrontal cortex. The val158 allele is associated with higher COMT activity than the met158 allele. Twenty-two volunteers genotyped for the COMT val158met polymorphism completed high and low gf versions of spatial and verbal problem-solving tasks. Our results showed a positive effect of COMT val allele load upon the blood oxygen level–dependent response in LPFC, pre-SMA/ACC, and IPS during high gf versus low gf task performance in both spatial and verbal domains. These results indicate an influence of the COMT val158met polymorphism upon the neural circuitry supporting gf. The behavioral effects of val allele load differed inside and outside the scanner, consistent with contextual modulation of the relation between COMT val158met genotype and gf task performance.