OBJECTIVE To investigate the combined effect of the apolipoprotein E epsilon4 (ApoE*4) allele and midlife cardiovascular risk factors on cognitive decline. METHODS Data are from the National Heart, Lung, and Blood Institute Twin Study-a longitudinal cardiovascular epidemiologic study of World War II male veteran twins currently in its 27th year of follow-up. Subjects were assessed for cardiovascular risk factors, including BP and glucose levels, at mean ages 48, 58, and 63 years. Participants in the current study are 410 individual twin subjects for whom cognitive function was measured twice, at ages 63 and 73 years. Ten-year change scores in performance on neuropsychological test examinations were adjusted for age, education, baseline score, and incident cardiovascular disease. RESULTS For the sample as a whole, we observed a significant decline (p < 0.01) in cognitive performance over the 10 years of follow-up. ApoE*4 carriers with midlife hyperglycemia experienced the greatest decline in performance, which was also greater than expected from the separate effects combined. Midlife hypertension and ApoE*4, were each associated with excess decline in performance on tests of psychomotor speed. Their joint effect, however, was not greater than expected from the separate effects combined. CONCLUSIONS ApoE*4 and midlife cardiovascular risk factors may have a synergistic effect on decline in cognitive function. This effect may be due to greater vascular or degenerative damage among subjects with ApoE*4.