The present invention provides methods and compositions for treating hypercholesterolemia using therapeutic apoE proteins. A therapeutic apoE protein is a naturally-occurring apoE protein (e.g., apoE1, apoE2, apoE2*, apoE2**, apoE3, and apoE4) that has one or more amino acid substitutions in the carboxy-terminal region which, when administered to a mammal having hypercholesterolemia, reduces the plasma cholesterol levels without inducing hypertriglyceridemia. The invention also provides a method for reducing plasma cholesterol using low doses of naturally-occurring apoE proteins.