Working memory-related brain activation has been widely studied, and impaired activation patterns have been reported for several psychiatric disorders. We investigated whether variation in N-back working memory brain activation is genetically influenced in 60 pairs of twins, (29 monozygotic (MZ), 31 dizygotic (DZ); mean age 24.4 ± 1.7S.D.). Task-related brain response (BOLD percent signal difference of 2 minus 0-back) was measured in three regions of interest. Although statistical power was low due to the small sample size, for middle frontal gyrus, angular gyrus, and supramarginal gyrus, the MZ correlations were, in general, approximately twice those of the DZ pairs, with non-significant heritability estimates (14–30%) in the low-moderate range. Task performance was strongly influenced by genes (57–73%) and highly correlated with cognitive ability (0.44–0.55). This study, which will be expanded over the next 3 years, provides the first support that individual variation in working memory-related brain activation is to some extent influenced by genes.