The effect of hypercholesterolemia induced immune response and inflammation on progression of atherosclerosis in ApoB ^tm25gy LDLr ^tm1Her mice, expressing only ApoB100 and deficient in the low density lipoprotein (LDL) receptor, thus closely resembling human cholesterol transport is not well defined. Atherosclerosis was induced by a high cholesterol diet and its progression was studied at 8, 14 and 20 weeks. Antibody response was determined by ELISA. Lymphocytes in spleen and aortic expression of inflammatory markers were studied by flow cytometry, and immunohistochemistry respectively. A rapid increase in plasma LDL levels in the first 8 weeks was followed by the exponential development of atherosclerosis between 8 and 14 weeks. Progression of the disease was accompanied by an accumulation of macrophages and increased expression of IL17 and IFN-γ in the aorta. Hypercholesterolemia resulted in increased immune response to modified lipids and aortic inflammation, with an expansion of Th17 cells in the spleen. Progression of atherosclerosis showed a positive correlation (r = 0.84, P < 0.001) with Th17 cells and a negative correlation with Treg cells (r = 0.83, P < 0.001). IgM antibodies to Ox-LDL and Th17 cells in spleen showed greatest association with disease development. Our results suggest that anti Ox-LDL IgM antibodies, Th17 cells could be developed as a potential marker to study disease progression and to study the effect of therapeutic regulation of inflammation.