Background: Atherosclerosis is considered analogous to chronic inflammatory diseases. Beta2-glycoprotein I (β2GPI) is a phospholipid binding protein shown to serve as a target for prothrombotic antiphospholipid antibodies. It has recently been demonstrated to drive an immune mediated reaction and enhance murine atherosclerosis. Oral tolerance is a method in which feeding a given antigen, downregulates the respective immune responses towards it, and attenuates concomitant organ specific disorders. Herein, we tested the hypothesis, that inhibiting cellular immunity to β2GPI would result in suppression of fatty streak formation in mice. Methods and results: LDL receptor deficient mice were fed different doses of human or bovine β2GPI or BSA and than switched to an atherogenic diet. To determine the effect of feeding on lymph node proliferative indices, separate groups of mice were fed β2GPI and then immunized with the respective antigen. Feeding either human or bovine β2GPI was effective in attenuating atherosclerosis as compared to control fed animals. Oral feeding with of β2GPI inhibited lymph node cell reactivity to β2GPI in mice immunized against the human protein. Oral tolerance was also capable of reducing reactivity to oxidized LDL in mice immunized against oxLDL. IL-4 and IL-10 production was upregulated in lymph node cells of β2GPI-tolerant mice immunized against β2GPI, upon priming with the respective protein. Conclusion: Thus, oral administration of β2GPI is an effective means of suppressing atherogenesis in mice and should further be investigated.