The hypolipidemic effects of lovastatin and clofibrate have been evaluated in 12 patients with type III hyperlipoproteinemia. In these patients plasma concentrations of total cholesterol decreased from 500 +/- 56 mg/dL (mean +/- SEM) at baseline to 278 +/- 23 mg/dL on lovastatin (20 mg twice daily), and were 299 +/- 15 mg/dL during treatment with clofibrate (1 g twice daily). Nine patients were treated sequentially with lovastatin at doses of 20 and 40 mg twice daily and clofibrate; in these patients total plasma cholesterol concentrations decreased from 549 +/- 67 mg/dL at baseline to 291 +/- 24 mg/dL on lovastatin (20 mg twice daily), 247 +/- 20 mg/dL (40 mg twice daily) and were 297 +/- 18 mg/dL on monotherapy with clofibrate. Concentrations of very-low-density lipoprotein (VLDL) cholesterol were similar on clofibrate and the higher dose of lovastatin, whereas concentrations of low-density lipoprotein (LDL) cholesterol were significantly lower on lovastatin. In six patients who remained hyperlipidemic on monotherapy with either drug, combination drug therapy with lovastatin (20 mg twice daily) plus clofibrate reduced plasma concentrations of total cholesterol from 635 +/- 79 mg/dL to 205 +/- 11 mg/dL. No patients were discontinued from single or combined drug therapy and no significant biochemical abnormalities were observed. The results of this study demonstrate the potential usefulness of lovastatin in the therapy of type III hyperlipoproteinemia and indicate that, in selected patients who remain hypercholesterolemic on monotherapy with either clofibrate or lovastatin, combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total, VLDL, and LDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)