Direct measurement by homogenous assays has recently been applied to measuring low-density lipoprotein-cholesterol (LDL-C) and has replaced the Friedewald calculation in Japan, but it remains unclear how direct measurement compares with the Friedewald calculation in evaluating hypercholesterolemia. The aim of this study was to determine the effect of the two methods on the diagnosis of hypercholesterolemia. In a total of 1655 workers from our institution (1451 men, 43.6 +/- 10.2 years; 204 women, 38.3 +/- 10.4 years), we investigated the LDL-C levels by the direct and Friedewald methods. In this study, we excluded workers whose triglyceride levels exceeded 400 mg/dl (n=18). Direct LDL-C showed a significantly positive correlation with Friedewald LDL-C (R2 = 0.975, P < 0.0001). On the other hand, the mean direct LDL-C was 5.9 mg/dl higher than the mean Friedewald LDL-C (126.7 +/- 30.6 mg/dl vs. 120.8 +/- 30.5 mg/dl, P < 0.0001), and direct LDL-C was higher in 89.1% of the study population. The frequency of study subjects diagnosed with hypercholesterolemia, defined as LDL-C > or =140 mg/dl, was significantly higher in the direct measurement than in the Friedewald calculation (31.7% vs. 25.1%, P < 0.0001). In conclusion, we demonstrated that the direct measurement showed a higher rate of hypercholesterolemia prevalence than the Friedewald calculation indicated. This result suggests that we have to give careful consideration to the method for measuring LDL-C in the clinical diagnosis and management decisions of hypercholesterolemia.