Fifty-seven healthy volunteers (mean age 46 yr) were fed for 45 days on diets containing 16% of energy as protein, 35% as fat (polyunsaturated/saturated fat ratio = 0.5) and about 375 mg cholesterol/day. Of the protein in the diets 60% was provided as caseinate, as soy protein isolate, or as soy protein concentrate. After a control period of 17 days during which all the subjects received the casein diet, 17 subjects continued on this diet for the next 28 days (test period), 20 subjects switched to the soy isolate diet, and the remaining 20 subjects switched to the soy concentrate diet. Serum cholesterol levels at the end of the control period were 207 +/- 36, 205 +/- 40, and 199 +/- 35 mg/dl (mean +/- SD) for the casein, isolate, and concentrate groups, respectively. Mean changes over the test period were -2 +/- 10, -8 +/- 12, and +1 +/- 10 mg/dl, respectively. Compared with the casein diet, the isolate diet caused a small, nonsignificant decline in both serum total cholesterol and low-density lipoprotein cholesterol (-6.5 mg/dl) and an increase in high-density lipoprotein cholesterol (+5.8 mg/dl) (p less than 0.05). These effects may have been more obvious if there had been no differences between groups in weight loss. No correlation was found between the response and the initial cholesterol level. No differences in lipoprotein composition were found between the casein and soy concentrate groups. Our data suggest that soy protein preparations do not have dramatic effects on the serum total cholesterol concentration in healthy subjects. However, pure soy protein might have some beneficial effect on the distribution of cholesterol over the lipoproteins. The lack of effect of the less refined soy protein concentrate suggests that the dietary fiber and other nonprotein components of soy concentrate do not have, at least in the short-term, a favorable effect on serum cholesterol and lipoproteins in healthy adults.