The IGF system has been implicated in cardiovascular disease (CVD) development. The prospective association of serum IGF-I and IGF-binding protein-1 (IGFBP-1) with all cause, ischemic heart disease (IHD), and non-IHD CVD mortality was examined in 633 men and 552 nonestrogen-using postmenopausal women, aged 51-98 yr (mean, 74 yr) in 1988-1992, who were followed through July 2001 (96% follow-up). During the 9- to 13-yr follow-up, there were 522 deaths; 224 were attributed to CVD, and 105 were caused by IHD. IGF-I and IGFBP-1 were independently and jointly related to risk of IHD mortality. In a proportional hazards model including both IGF-I and IGFBP-1 and adjusting for CVD risk factors, the relative risk of IHD mortality was 38% higher for every 40 ng/ml (1 SD) decrease in IGF-I (95% confidence interval, 1.09-1.76; P = 0.005) and 3.11 times greater for those in the lowest quintile of IGFBP-1 (95% confidence interval, 1.74-5.56; P < 0.001) compared with those with higher IGFBP-1 levels. IGF-I and IGFBP-1 (alone or in combination) were not related to risk of all cause or non-IHD CVD mortality. We conclude that low baseline levels of IGF-I and IGFBP-1 increase the risk of fatal IHD among elderly men and women independent of prevalent IHD and CVD risk factors.