The hypocholesterolemic and adverse effects of colestipol, 20 g/day, and colestipol, 10 g/day combined with probucol, 1 g/day, were compared. A double-placebo, diet-controlled, crossover trial that lasted 19 months was undertaken on 22 hypercholesterolemic patients who had low-density lipoprotein (LDL) cholesterol levels greater than 180 mg/dl after 3 months of diet and placebo treatment. Uniformity of diet and physical activity were monitored throughout the study. Compared with baseline values after 3 months on diet-placebo treatment, "combined" therapy reduced LDL cholesterol by more than 20% in 15 patients, more than 25% in 9 patients and more than 45% in 2 patients. Treatment with "half-dose" colestipol and probucol resulted in the greatest mean LDL cholesterol reduction, from 239 mg/dl during diet-placebo period to 170 mg/dl; the difference was not statistically significantly different from the reduction to 180 mg/dl with 20 g of colestipol alone. Fifteen patients showed the greatest reduction in LDL cholesterol after combined therapy. Probucol produced statistically significant reductions in very low density lipoprotein and high-density lipoprotein cholesterol. The major gastrointestinal side effects of single therapy with colestipol (constipation) and probucol (diarrhea) were ameliorated or abolished by concomitant administration. Probucol-colestipol co-administration allowed a 50% reduction in the colestipol dosage, with similar efficacy and improved tolerability and reduced mean serum LDL cholesterol with a frequency and magnitude rarely seen with other hypocholesterolemic treatments. Hypercholesterolemic persons who cannot tolerate full doses of resins may receive equal benefit by half the dose if probucol is added to the regimen.