To study the expression of extrahepatic apolipoprotein E (apoE) under hypercholesterolemic conditions, apoE mRNA levels were evaluated in 14 tissues of rabbits fed on a cholesterol rich diet and compared to age-matched control animals. In hypercholesterolemic rabbits apoE expression was significantly induced in adipose tissue, adrenals, aorta, lung and spleen. The increase in apoE mRNA levels in lung and spleen was associated with the presence of cholesterol-loaded macrophages. These cells were found to express high levels of apoE mRNA as demonstrated by in situ mRNA hybridization. Our results suggest that extrahepatic tissues would be partially responsible for the rise in serum apoE levels detected under hypercholesterolemic conditions.