Background: Despite their advantages, percutaneous coronary interventional (PCI) procedures are less effective in diabetic patients. Changes in the mechanical properties of vascular walls secondary to long-term hyperglycemia as well as other factors such as age may influence coronary distensibility. This investigation is aimed at deciphering the extent of these effects on distensibility of post-mortem human coronary arteries in a controlled manner. Methods and Results: Excised human left anterior descending coronary arteries (LAD) were obtained within 24 hours post mortem. Using intravascular ultrasound, IVUS, vascular deformation was analyzed at mid-regions of 51 moderate lesions. Intraluminal pressure was systematically altered using a computerized pressure pump system, and monitored by a pressure sensing guidewire. Distensibility, a normalized compliance term, was defined as the change in lumen area normalized by the initial reference area, over a given pressure interval. Using multivariate analysis, repeated measures ANOVA, coronary distensibility was independently influenced by hyperglycemia, and age (p<0.05) through the entire pressure range. Within physiological pressure range, distensibility was significantly reduced with age in non-hyperglycemic coronary specimens (10.55 ± 4.41 vs. 6.99 ± 2.45, x10³ kPa^-1, p=0.01), while the hyperglycemic vessels were stiff even in the younger group (7.90 ± 5.82 vs. 7.20 ± 3.36, x10³ kPa^-1, p=0.79). Similar results were observed with stiffness index ()and elastic modulus (E) of the arteries. Conclusions: Hyperglycemia and age independently influenced the distensibility of moderately atherosclerotic LAD coronary arteries. The stiffening with age was overshadowed in the hyperglycemic group by as yet undetermined factors.