Cholesterol-fed rabbits are more susceptible to experimental infections than similar animals given a normal diet. Multiple tests were employed to estimate functions of reticuloendothelial (RE) phagocytosis, lymphocyte activity, polymorphonuclear (PMN) and macrophage chemotaxis, phagocytosis, and bactericidal activity, as well as enzymatic activity of the macrophages. RE phagocytosis was unchanged in the cholesterol-fed animals. However, most functions of the isolated PMNs and macrophages were significantly reduced. Three of five dehydrogenases and phosphatase were lower in activity from cells obtained from cholesterol-fed rabbits than from controls. Conversely, both B and T lymphocyte activities were significantly higher among the cholesterol-fed animals. These metabolic and functional alterations of cells from cholesterol-fed rabbits may explain the increased susceptibility to infection among these animals. The enzymatic changes found in leukocytes may correlate with those changes in arteries observed during atherogenesis, thereby providing a new prognostic test for risk of atherosclerosis.