Objective: Because low density lipoprotein-cholesterol (LDL-C) is a modifiable risk factor for coronary artery disease (CAD), its routine measurement is recommended in the evaluation and management of hypercholesterolemia. Concentrations of LDL-C are commonly monitored by means of the Friedewald formula (FF), which provides a relative estimation of LDL-C concentration when the triglyceride (TGs) concentration is <200 mgr/dl and there are no abnormal lipids. Because of the limitations of the Friedewald calculation, direct methods for an accurate quantification of LDL-C are needed. Methods: We critically examined an immunoseparation method for direct assay of LDL-C in a comparison with FF. 1) We measured intraassay and interassay precision using quality-control sera and patient serum pools. Accuracy was evaluated from total error analyses. Sample stability was examined over 2 months. 2) The LDL-C levels obtained with direct assay were compared with those calculated by the FF in 47 randomly chosen patient samples. The samples were classified as group 1 (patients with TGs 60-308 mg/dl n=25) and group 2 (patients with TGs 320-695 mg/dl, n=22). Results: The direct immunoseparation assay displayed an excellent precision (total coefficient of variance (CV) <2.5%, intraassay CV<1.5% and interassay CV<1.5%). Mean total error was 4.34%. The direct assay met the current National Cholesterol Education Program (NCEP) requirements for LDL-C testing for precision and accuracy. The results of direct method (x) and the FF (y) were highly correlated (r=0.9908, y=1.030x-0.289, n=25) in group 1, but the results of two methods disagreed (r=0.716, y=0.956x-24.869, n=22) in group 2 (patients with TGs 320 -695 mg/dl). Conclusion: The direct immunoseparation assay meets the currently established analytical performance goals and may be useful for the diagnosis and management of hyperlipidemic patients.