Eighty New Zealand rabbits in eight groups (10 each) were fed a 0.5% cholesterol diet for 12 weeks. One group served as a control and was sacrificed at the end of 12 weeks. Seven other groups were shifted to a normal diet and received a drug(s) or placebo for the second 12 weeks. The high dose of etidronate (3 mg/kg/day) with lovastatin (6 mg/kg/day) significantly reduced the percent of aortic atherosclerotic lesions [56 +/- 21 vs. 77 +/- 17% (mean +/- SD), p < 0.05] in the regression study. Compared to the control groups for etidronate and lovastatin, the high or low dose (0.15 mg/kg/day) of etidronate significantly reduced aortic standardized plaque volume per unit (18.7 +/- 7.9 or 18.8 +/- 9.1 vs. 28.4 +/- 11.8 mm.%, p < 0.05). Lovastatin reduced pulmonary artery maximum plaque thickness (0.13 +/- 0.10 vs. 0.23 +/- 0.11 mm, p < 0.05). There were no differences in serum lipid and calcium levels in the control and treated groups. The high dose of etidronate inhibited bone mineralization as expected, whereas the low dose of etidronate did not. These data suggest that etidronate with lovastatin can regress aortic atherosclerosis in the cholesterol-fed rabbit placed on a normal diet.