To investigate the high incidence of atherosclerosis in the patients affected with rheumatoid arthritis, we examined the effect of feeding a cholesterol-enriched diet on the development of hypercholesterolemia in pX transgenic mice, which spontaneously develop chronic inflammatory arthritis. Cholesterol feeding to pX transgenic mice induced a striking elevation in serum total cholesterol (ca. 500 mg/dl) compared with their littermates, BALB/c mice used as controls. The pX transgenic mice exhibited elevated mRNA levels of ACAT1, and ABCG5 in the small intestine compared with their littermates, and furthermore, apoA1, ABCA1, ABCG5, ACAT1, and ACAT2 mRNAs were induced more easily by a cholesterol-enriched diet in pX transgenic mice than their littermates. As ACAT1 mRNA in the small intestine is known not to be induced by feeding a cholesterol-enriched diet, a possibility was inferred that interferon-gamma induced by Tax, a pX gene product, might play an important role in the induction of ACAT1 mRNA and the following hypercholesterolemia. These findings suggest that pX gene plays an important role in inducing hypercholesterolemia in BALB/c mice, which are genetically less susceptible to hypercholesterolemia and atherosclerosis and that RA patients carrying HTLV-1 virus have a predilection for hypercholesterolemia, a main risk factor for cardiovascular diseases.