Previous studies have shown that congenic bone marrow transplantation into apolipoprotein E-deficient mice prevented hypercholesterolemia and atherosclerosis. In this study, we examined the effect of intravenous administration of human umbilical cord blood (HUCB) mononuclear cells on the progression of atherosclerosis in male homozygous mice that had mutation in the low-density lipoprotein receptor (Ldlr(tm1Her) mutation mice). In addition, the effect of human breastmilk alone as well as the combination of HUCB cells and breastmilk was studied on the prevention of atherosclerosis in these mice. In all groups of mice, atherosclerosis was predominant in the ascending aorta, but the rest of the aorta had variable evidence of atherosclerosis. Treatment of mice with HUCB cells significantly ameliorated the development of atherosclerosis in the ascending aorta, as compared with untreated mice; whereas breastmilk alone did not have any significant effect. A similar beneficial effect was observed with the combination therapy, which could be attributed only to HUCB cell treatment. There was no beneficial effect of treatment on the thoracic and abdominal aorta. Thus, early administration of HUCB cells prevents the progression of atherosclerosis in the ascending aorta of mice that are prone to the development of atherosclerosis. This beneficial effect occurred without any immunosuppression and graft-vs-host disease.