This study assessed the response of lysyl oxidase, the enzyme that initiates covalent crosslinking in elastin and collagen, by studying the aortic tissue of rabbits after arteriosclerosis had been induced by diet. Rabbits in the experimental group were fed an atherogenic diet of rabbit chow supplemented with 8% peanut oil and 2% cholesterol for varying periods of time, while the control group was fed only rabbit chow. Lysyl oxidase activity was found to be distributed throughout the length of the thoracic and abdominal aortas of the normal rabbits. However, rabbits fed the atherogenic diet showed marked increases in enzyme activity in the aortic arch, a change that was initially evident after 30 days and became greatest (2.5 times that of the controls) after 90 days. Enzyme activity in the study rabbits increased only minimally in the abdominal aortic wall. Aortic prolyl hydroxylase activity measured after 60 days of feeding changed in degree and manner similar to lysyl oxidase activity. These region-specific changes in enzyme activities correlated with the distribution and severity of aortic lesions in this model of the disease. Lysyl oxidase activity increased dramatically in this model of atherosclerosis, suggesting that this extracellular enzyme activity may prove to be a vulnerable and accessible point of control of the fibrotic response in atherosclerosis. (Arteriosclerosis 1981; 1:287-291)