Background: Nattokinase is a fibrinolytic enzyme isolated from the vegetable cheese natto. Although research suggests that nattokinase has beneficial effects on lipid metabolism, there is no clinical data on its effects in human patients with hypercholesterolemia. Methods: Thirty patients with primary hypercholesterolemia given instruction on a low cholesterol diet and treated with 400 mg (4000FU) nattokinase or placebo twice daily for 8 weeks were selected. Results: No significant changes in serum triglyceride, non-HDL cholesterol, total cholesterol/HDL ratio, and LDL/HDL ratio were found in either treatment group. There was a tendency of greater reduction of total serum cholesterol in nattokinase group than placebo group (-6.15% and -6.8% after 4 and 8 weeks treatment, respectively). There were also greater reduction of HDL-C and LDL-C after 8 weeks in nattokinase group (-10.85%, -6.3% respectively) but no statistically significant was noted. Conclusion: In adults with primary hypercholesterolemia, nattokinase is well tolerated and in combination with low cholesterol diet may have effects on the serum cholesterol profile.