Over the last decade there has been increasing awareness that some cardiovascular medications may adversely affect serum cholesterol concentrations. It has been suggested previously that amiodarone may alter serum cholesterol, triglyceride and glucose concentrations, but no substantive data support this observation. During the course of a 1-year study of adverse effects in patients taking amiodarone, 21 patients with normal total serum cholesterol before entry in the study were prospectively investigated for changes in lipid metabolism. A statistically significant sustained rise of 17% in total serum cholesterol occurred from a baseline of 178 +/- 7 mg/dl (4.6 +/- 0.2 mmol/liter) to 208 +/- 9 mg/dl (5.4 +/- 0.2 mmol/liter). Ten of the patients developed elevations of cholesterol above the 75th percentile for their age and sex. This group experienced a sustained rise of 20% in mean cholesterol concentration from baseline, had statistically significant elevations of triglyceride concentrations and had higher glucose and desethylamiodarone concentrations than patients who did not develop elevations in cholesterol greater than the 75th percentile. It may be possible to predict these differences in response as early as 4 to 8 weeks after starting therapy. Because amiodarone is increasingly used in patients without ischemic heart disease or life-threatening arrhythmias, the potential atherogenic risk of these metabolic abnormalities merits further investigation.