Atherosclerosis is a disease associated with aging and is subject to modulation by both the innate and adaptive immune system. The time course of age dependent changes in immune regulation in the context of atherosclerosis has not been characterized. This study aims to describe the alteration of the immune responses to oxLDL during aging that is associated with changes in plaque size and phenotype in apo E (-/-) mice. Mice fed Western diet were euthanized at 15-17, 36 or >52 weeks of age. The descending aortas were stained for assessment of extent of atherosclerosis. Plaque lipid, macrophage and collagen content were evaluated in the aortic sinus lesions. Adaptive immune response to oxLDL was assessed using anti malondialdehyde oxidized (MDA)-LDL and copper oxidized (Cu-oxLDL) IgG, and innate immune response using anti Cu-oxLDL and phosphorylcholine (PC) IgM. Aging was associated with a significant increase in plaque area and collagen content and a decrease in plaque macrophage and lipid content. MDA-LDL IgG significantly increased at 36 weeks but was reduced in mice >52 weeks. Cu-oxLDL IgG increased with age and IgG-apoB immune complexes were increased in the >52 weeks group. Cu-oxLDL and PC IgM significantly increased with age. The expression of splenic cytokines such as IFN-, IL-4 and IL-10 increased with age. Our study shows generalized increase in innate immune responses associated with progression of atherosclerosis and a less inflammatory and less lipid-containing plaque phenotype during aging. The adaptive immune response appeared to be less generalized, with a specific reduction in MDA-LDL IgG.