Bone-derived undercarboxylated osteocalcin regulates insulin secretion and sensitivity in mice, and reduced serum total osteocalcin (TOC) is associated with diabetes in humans. However, the relationship between TOC levels and other cardiovascular risk factors is uncertain. We sought to determine whether serum TOC is associated with metabolic syndrome and its components in older men. Cross-sectional analysis from a population-based cohort of men aged >or=70 years. Early morning sera were assayed for TOC. Insulin resistance was estimated using a homeostatic model (HOMA2-IR). Metabolic syndrome was defined according to NCEP-ATPIII criteria. TOC was assayed in 4047 men. Men who were not fasting and reported having bone fractures, Paget's disease, or bisphosphonate, glucocorticoid, or warfarin use were excluded, leaving 2765 men with metabolic syndrome present in 797 (28.8%). TOC was inversely associated with waist circumference, glucose, and triglyceride levels and HOMA2-IR (all P<0.001), and was lower in men with metabolic syndrome (mean+/-S.E.M.: 20.1+/-0.4 vs 21.4+/-0.2 microg/l, P=0.002). In multivariate analysis, men with TOC of 13.25-16.55 and <13.25 microg/l had 1.5- to 2-fold increased risk of metabolic syndrome compared with men with levels >or=30 microg/l. TOC remained associated with metabolic syndrome after adjustment for individual components, but not after adjusting for both waist circumference and glucose. Increased waist circumference, reduced TOC, elevated glucose, and triglyceride levels are inter-related in aging men. Osteocalcin may lie in the causal pathway between central adiposity and insulin resistance. Further research is required to evaluate whether interventions which raise osteocalcin levels might decrease cardiovascular risk.