This study was carried out to determine whether the decrease in plasma cholesterol produced by 5-year probucol administration would prevent development of myocardial infarction in patients with heterozygous familial hypercholesterolemia. Treated and untreated (control) groups included 39 and 91 patients, respectively. There were no differences in initial levels of total cholesterol (TC), low-density-lipoprotein (LDL)-cholesterol or high-density-lipoprotein (HDL)-cholesterol between groups. There were also no differences in age or incidence of risk factors at the beginning of the study. Probucol decreased levels of TC, LDL-cholesterol, and HDL-cholesterol by 23%, 24%, and 21%, respectively. Mean Achilles tendon thickening decreased from a median of 10.0 mm (range, 5.0 to 25.0 mm) to a median of 8.0 mm (range, 4.0 to 15.0 mm) over 5 years. Master double tolerance tests changed from positive to negative in five of 39 patients, and no patient experienced deterioration. There was no new episode of myocardial infarction in the treated group. Three cases of myocardial infarction were observed in the control group during the study. Results suggest that probucol administration might prevent development of myocardial infarction in patients with familial hypercholesterolemia.