In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a 19% lower incidence of coronary heart disease (CHD) in cholestyramine-treated men was accompanied by mean falls of 8% and 12% in plasma total (TOTAL-C) and low-density lipoprotein (LDL-C) cholesterol levels relative to levels in placebo-treated men. When the cholestyramine treatment group was analyzed separately, a 19% reduction in CHD risk was also associated with each decrement of 8% in TOTAL-C or 11% in LDL-C levels (P less than .001). Moreover, CHD incidence in men sustaining a fall of 25% in TOTAL-C or 35% in LDL-C levels, typical responses to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at pretreatment levels. Adherence to medication was associated with reduced incidence of CHD only when accompanied by falls in TOTAL-C and LDL-C levels. Small increases in high-density lipoprotein cholesterol levels, which accompanied cholestyramine treatment, independently accounted for a 2% reduction in CHD risk. Thus, the reduction of CHD incidence in the cholestyramine group seems to have been mediated chiefly by reduction of TOTAL-C and LDL-C levels.