Background: Animal and clinical experiments revealed conflicting results as to the effect of bisphosphonate (BP) on atherosclerosis and related vascular calcification. Although apolipoprotein E-deficient (apoE-/-) mice is a well-known atherosclerosis model very similar to human, there was only one report to investigate the effect of BP in apoE-/- mice, in which alendronate and risedronate administrated for 8 weeks from 16-week-old unexpectedly caused arterial inflammation and plaque rupture. Zoledronic acid (ZA), a novel nitrogen-containing BP, is one of the most potent agents for blocking osteoclast function, has the longest half-life and can be administrated by intravenous route. However, it has been rarely evaluated for anti-atheroscleortic effects. Objectives: Our goal was to investigate the effects of ZA on the formation of atheromatous plaque in apoE-/- mice with different age. Methods and Results: All apoE-/- mice were fed normal chow diet during the study period. ZA (0.1mg/kg) was administrated by single injection via tail vein to 8-week-old apoE-/- mice (ZA8 group, n=4) and 16-week-old apoE-/- mice (ZA16 group, n=5). Histological evaluation at 32 weeks of age revealed that four of five (80%) control apoE-/- mice had typical plaque in aortic root section, whereas ZA16 group had it in 40% and there was no atheromatous plaque in ZA8 group (0%). At 32 weeks, there was no difference in bone mineral density of three groups, but serum calcium, phosphate, and osteopontin levels were significantly higher in ZA-treated groups than control mice. Serum lipid levels and inflammatory markers were not significantly different among three groups, though IL-6, TNF-慣, and MCP-1 showed a trend for decrease in ZA-treated groups as compared with control mice. Conclusions: These findings suggest that ZA can be a novel drug to prevent the formation of atheromatous plaque in apoE-/- mice and that the effect is different according to the age at ZA administration.