Context: Numerous studies have investigated the effect of serum IGF-I concentration on aging and different aging-related diseases, e.g. cardiovascular disease (CVD) and cancer. Decreased as well as increased levels have been reported to be associated with reduced life expectancy in humans. Objective: This study investigates the association of serum IGF-I concentration with all-cause and cause-specific mortality of community-dwelling older persons and the development of CVD and cancer. Design, Setting, and Participants: Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing multidisciplinary cohort study in the general Dutch population of older persons (≥65 yr old) where serum IGF-I was measured (n = 1273). The mortality information was ascertained using the International Classification of Diseases, 10th revision, and the presence or absence of CVD and cancer by self-reports with a follow-up of 11.6 yr. Main Outcome Measure: We measured all-cause, CVD, and cancer mortality and nonfatal CVD and cancer. Results: Fully adjusted Cox proportional hazards models demonstrated an increased risk of all-cause mortality for older persons with IGF-I values in the lowest quintile as compared to the middle quintile [hazard ratio (HR), 1.28; 95% confidence interval (CI), 1.01-1.63]. A more than 2-fold increased risk of CVD mortality was revealed for both low-normal (HR, 2.39;95% CI, 1.22-4.66) and high-normal (HR, 2.03; 95% CI, 1.02-4.06) IGF-I values. Significant associations of serum IGF-I with nonfatal CVD and fatal and nonfatal cancer were not observed. Conclusions: Results suggest a U-shaped relationship between IGF-I level and mortality, with fatal CVD as the most critical outcome in community-dwelling older persons. Copyright © 2010 by The Endocrine Society.