Hypercholesterolemia, a significant cardiovascular risk factor, is prevalent in the American population. Many drugs lower circulating cholesterol levels, but they are not infrequently associated with severe side effects. Accordingly, natural means to lower cholesterol levels safely would be welcomed. We examined 40 hypercholesterolemic subjects (total cholesterol 210-300 mg/dL) in a randomized, double-blind, placebo-controlled study. The four groups of ten subjects received either placebo bid, chromium polynicotinate (Cr) 200 microg bid, grape seed extract (GSE) 100 mg bid, or a combination of Cr and GSE at the same dosage bid. Over two months, the average percent change +/- SEM in the total cholesterol from baseline among groups was: placebo -3.5% +/- 4, GSE -2.5% +/- 2, Cr -10% +/- 5, and combination -16.5% +/- 3. The decrease in the last group was significantly different from placebo (p < 0.01). The major decrease in cholesterol concentration was in the LDL levels: placebo -3.0% +/- 4, GSE -1.0% +/- 2.0, Cr -14% +/- 4.0, and the combination -20% +/- 6.0. Again, the combination of Cr and GSE significantly decreased LDL when compared to placebo (p<0.01). HDL levels essentially did not change among the groups. Also, there was no significant difference in the triglyceride concentrations among the groups; and no statistically significant differences were seen in the levels of autoantibodies to oxidized LDL (Ox-LDL). However, the trend was for the two groups receiving GSE to have greater decreases in the latter parameter, i.e., -30.7% and -44.0% in the GSE and combined groups in contrast to -17.3% and -10.4% in the placebo and chromium groups. We determined the number of subjects in each group who decreased autoantibodies to oxidized LDL greater than 50% over eight weeks and found these ratios among groups: placebo = 2/9, Cr = 1/10, GSE = 6/10, and combined = 3/8. Thus, 50% of subjects (9/18) receiving GSE had a greater than 50% decrease in autoantibodies compared to 16% (3/19) in the two groups not receiving GSE. No significant changes occurred in the levels of circulating homocysteine and blood pressure among the four groups. We conclude that a combination of Cr and GSE can decrease total cholesterol and LDL levels significantly. Furthermore, there was a trend to decrease the circulating autoantibodies to oxidized LDL in the two groups receiving GSE.