Context: Circulating IGF-I is inversely associated with ischemic heart disease incidence. Whether this association relates to alterations in plaque growth or stability, and the role of IGF-II and the major binding proteins [IGF binding protein (IGFBP)-2 and -3], is unclear.

Objective: Our objective was to test the hypothesis that circulating IGF-I is inversely, and IGF-II is positively, associated with subclinical atherosclerosis and plaque stability.

Design, Setting, and Participants: This was a cross-sectional analysis based on 310 participants in the United Kingdom-based Boyd Orr cohort who were aged 63–82 yr. Cohort members from Aberdeen, Bristol, Dundee, Wisbech, and London were invited to clinics for fasted venepuncture and arterial ultrasound examination.

Main Outcomes: Arterial intima-media thickness, arterial plaque prevalence, and computerized assessment of plaque echogenicity (a measure of stability), undertaken using the gray scale median, were calculated.

Results: In total, 269 of 310 (86.8%) participants had at least one carotid or femoral plaque. In models controlling for IGFBP-3, there was a 44% (95% confidence interval 12–64%) reduction in the odds of any plaque and a 28% lower (0–48%) odds of echolucent (unstable) plaques per sd increase in IGF-I. IGFBP-3 was positively associated with plaque instability (odds ratio: 1.38; 0.99–1.93). IGF-II was positively associated (0.05-mm increase per sd; 95% confidence interval 0.01–0.09), and IGFBP-2 was inversely associated, with carotid bifurcation intima-media thickness. Neither IGF-II nor IGFBP-2 was associated with plaque prevalence or echogenicity.

Conclusion: High-circulating IGF-I levels may promote arterial plaque stability. IGF-II and IGFBP-2 do not appear to play a role in plaque development or stability.