Human atherosclerotic plaques contain significant numbers of T lymphocytes and monocyte-derived macrophages. Cytokines released from activated T lymphocytes induce aberrant expression of major histocompatibility complex class II (Ia) antigens by vascular smooth muscle cells and may also regulate cell proliferation and metabolism in the vessel wall. We have analyzed the arteries of cholesterol-fed rabbits to study the sequence of lymphocyte and monocyte entry into the forming atherosclerotic lesion. Rabbits were fed 0.3% cholesterol for 1-10 weeks, and monoclonal antibodies to rabbit leukocyte differentiation antigens and Ia antigen were applied to sections of the aorta. Monocytes were already observed 1 week after initiation of cholesterol feeding, and they accumulated in the intima, where they formed the bulk of the foam cell-rich lesion. T lymphocytes also adhered to the aortic surface from 1 week onward, and also accumulated in the lesion, although in lower proportions than did monocytes. In 10-week lesions, approximately 6% of cells expressed the T-lymphocyte marker L11/135. Ia antigen expression was frequent throughout the lesion in all phases of its development, and most of the Ia-expressing cells could be identified as monocyte-derived macrophages. These data indicate that the cholesterol-fed rabbit is a useful model for studying the role of monocytes and T lymphocytes in atherosclerosis.