We evaluated the performance of a direct Liquid N-geneous HDL-C assay (N-HDL; Genzyme Diagnostics, Cambridge, Mass) and compared it with a Centers for Disease Control and Prevention (CDC) modified reference procedure (M-REF) and phosphotungstic acid (PTA) precipitation method in patients with normotriglyceridemia (triglyceride level, <400 mg/dL) and hypertriglyceridemia (triglyceride level, > or =400 mg/dL). Excellent intra-assay and interassay coefficients of variation were obtained (<2.0%) using the N-HDL assay. The N-HDL and PTA assays correlated well with M-REF in normotriglyceridemic samples. In hypertriglyceridemic samples, however, the N-HDL method exhibited better correlation with M-REF than the PTA assay. In addition, compared with M-REF, the mean absolute percentage bias of N-HDL was lower than the PTA assay in normotriglyceridemic (4.9% vs 5.8%) and hypertriglyceridemic (5.4% vs 12.9%) samples. Hemolysis, ascorbic acid, and bilirubin did not interfere with the N-HDL assay. On the basis of these findings, the N-HDL assay compares favorably with the modified CDC reference method and seems superior to the PTA assay. It also has the advantage of being suited for complete automation and, thus, would prove useful in large clinical laboratories.