The Wisconsin Card Sorting Test (WCST) has been utilized extensively as a measure of executive function and working memory and as a neurocognitive probe of prefrontal brain function. In studies of psychiatric illness—particularly schizophrenia—it has also been considered to be a cognitive vulnerability marker or endophenotype. Heritability is an important criterion for an endophenotype, but the very few studies of the heritability of the WCST have yielded inconsistent results. The goal of this study was to investigate the extent to which genetic and environmental factors influence WCST performance in a large adult twin sample. A computerized WCST was administered to 660 middle-aged male twins (170 monozygotic pairs and 160 dizygotic pairs). Polychoric intrapair correlations for six WCST scores were compared between MZ and DZ twins in order to assess heritability. Correlations were relatively low and there were no significant MZ–DZ differences. To our knowledge, this is the largest twin study of the WCST to date. There was no evidence for heritability of the WCST in this midlife adult sample. The WCST remains a valuable research tool, and we do not think that one should conclude from these results that genetic influences on frontal-executive function are unimportant. Rather, we believe that our results suggest that some properties of this particular test make it undesirable for use as an endophenotype. © 2007 Wiley-Liss, Inc.