Individuals with familial hyperbetalipoproteinemia are at increased risk of premature atherosclerosis and thrombosis. Although there is controversy whether platelet survival is shortened or normal in this disease, several in vitro tests of platelet function after stimulation with ADP including electrophoretic migration, platelet factor 3, aggregation response and release of nucleotides have been found to be increased. These functional changes are accompanied by an increase of cholesterol to phospholipid ratio in the platelet membrane. Clofibrate and halofenate reverse some of these abnormalities in vitro and the former drug, when administered for 6 weeks to patients with type IIa hyperlipoproteinemia decreases platelet sensitivity to ADP and epinephrine. The platelet hypersensitivity to aggregating agents can be reproduced in vitro by increasing the cholesterol to phospholipid rather in normal platelets. These artificially hypersensitive platelets can be returned to normal by halofenate in vitro. Incorporation of cholesterol into platelet membranes increases the basal level of the membrane associated enzyme adenylate cyclase. However, the enzyme no longer responds to stimulation by prostaglandin E1, and this is associated with relative resistance of the platelet to inhibition by this pharmacologic agent. These functional alterations produced by cholesterol enrichment of platelet membranes occur in parallel with an increase in platelet membrane microviscosity suggesting that the more rigid membrane can alter the behavior cf membrane associated enzymes and receptors.