Objective: CD73 is an ectonucleotidase which catalyzes the conversion of AMP (adenosine monophosphate) to adenosine. Adenosine has been shown to be anti-inflammatory and vasorelaxant. The impact of ectonucleotidases on age-dependent atherosclerosis remains unclear. Our aim was to investigate the role of CD73 in age-dependent accumulation of atherosclerosis. Approach and results: Mice doubly deficient in CD73 and ApoE (apolipoprotein E; ( cd73 − /− /apoE −/− ) were generated, and the extent of aortic atherosclerotic plaque was compared with apoE −/− controls at 12, 20, 32, and 52 weeks. By 12 weeks of age, cd73 −/− /apoE −/− mice exhibited a significant increase in plaque (1.4±0.5% of the total vessel surface versus 0.4±0.1% in apoE −/− controls, P <0.005). By 20 weeks of age, this difference disappeared (2.9±0.4% versus 3.3±0.7%). A significant reversal in phenotype emerged at 32 weeks (9.8±1.2% versus 18.3±1.4%; P <0.0001) and persisted at the 52 week timepoint (22.4±2.1% versus 37.0±2.1%; P <0.0001). The inflammatory response to aging was found to be comparable between cd73 −/− /apoE −/− mice and apoE −/− controls. A reduction in lipolysis in CD73 competent mice was observed, even with similar plasma lipid levels ( cd73 −/− /apoE −/− versus apoE −/− at 12 weeks [16.2±0.7 versus 9.5±1.4 nmol glycerol/well], 32 weeks [24.1±1.5 versus 7.4±0.4 nmol/well], and 52 weeks [13.8±0.62 versus 12.7±2.0 nmol/well], P <0.001). Conclusions: At early time points, CD73 exerts a subtle antiatherosclerotic influence, but with age, the pattern reverses, and the presence of CD73 promoted suppression of lipid catabolism.