A comprehensive clinical evaluation of the effects of combined probucol-colestipol therapy was undertaken in 71 hypercholesterolemic patients. In the first 18-month double-blind, double-placebo, crossover study, the effects of 1 g/day of probucol and 20 g/day of colestipol were compared with the drugs used singly in 47 patients. The combination decreased low density lipoprotein (LDL) cholesterol from a diet-placebo baseline of 242 +/- 51 mg/dl to 171 +/- 41 mg/dl. LDL cholesterol levels were decreased by more than 30% in 49% of patients, and by more than 40% in 17% of patients. Combined drug use eliminated the gastrointestinal side effects of single-drug administration or diminished their severity. Twenty-two patients who complained of resin-induced constipation entered a 19-month continuation trial that called for a half-dose of colestipol during combination treatment. This therapy decreased the LDL baseline level of 239 +/- 46 mg/dl by more than 25% in 41% of patients, and by more than 45% in 9% of patients. All patients were able to tolerate the modified probucol-colestipol therapy. Finally, a comparison was made between the hypocholesterolemic effects of combined probucol-colestipol therapy obtained after 1 and 3 years in 24 patients. These were sustained in all but 5 patients. Combined probucol-colestipol therapy increases the hypocholesterolemic effects and decreases the gastrointestinal side effects of either drug used alone. In patients who cannot tolerate full doses of resin, a half-dose may render the drug more acceptable without diminishing its lipid-lowering effect.