1. In a new animal model which mimics the cellular events of early human atherosclerosis, atheroma-like lesions were produced by positioning a hollow silastic collar around the common carotid arteries of rabbits. The functional significance of these arterial lesions on blood flow responses to vasoactive agents was then studied in anaesthetized rabbits in vivo. 2. After 1 week of lesion development, resting blood flow was lower in atherosclerotic (cuffed) carotid arteries compared with the contralateral, sham-operated control arteries. 3. Intra-carotid injection of serotonin (0.01-1 microgram) produced dose-dependent increases in blood flow in control arteries, but produced either smaller increases or decreases in flow in cuffed arteries. Serotonin caused complete vasospasm (zero blood flow) in one of six rabbits. 4. Acetylcholine (0.0001-0.01 microgram, intra-carotid) produced smaller increases in blood flow in cuffed arteries compared with controls. 5. These data support the proposal that morphological and functional alterations in large arteries in the early stages of atherogenesis play an important role in determining blood flow in vivo. The increased vascular reactivity to serotonin which accompanies development of the lesions might contribute to vasospasm.