Aortic areas predisposed to early atherosclerosis in swine demarcated by Evans blue uptake (blue areas) show preferential intimal penetration by blood monocytes before and during lesion formation. These cells are thought to be the major source of foam cells in these early lesions. To examine mechanisms controlling monocyte migration into these areas, extracts of aortic tissue from both blue and white areas of hypercholesterolemic (H) and normal (N) swine were tested for chemotactic activity against monocytes from N and H swine and neutrophils from H swine. The data indicate that extracts of blue areas from H swine contained at least one, and possibly two, factors chemotactic only for monocytes from H swine, but not N swine. These factors were not present in similar extracts from white areas of H swine, or either blue or white area extracts from N swine. Gel filtration chromatography of crude blue area extracts separated two chemotactically active fractions of molecular weights 68,000 and 5000 that were not present in white area extracts and that elicited a positive chemotactic effect only for H swine monocytes. These findings provide a mechanism explaining our previous findings of preferential monocyte adhesion and intimal penetration in lesion-prone areas, and indicate that control of monocyte recruitment into the artery involves not only alteration of the arterial wall, but also functional changes in the circulating monocyte.