Current lipid guidelines recommend that therapy be targeted primarily at low-density lipoprotein (LDL) cholesterol, and that other lipid indexes may be used as secondary or supplementary targets. Emerging data have suggested that measures such as non-high-density lipoprotein (HDL) cholesterol, apolipoprotein-B, or the total/HDL cholesterol ratio may be more predictive of cardiovascular risk than LDL cholesterol. We conducted a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey to directly compare the strengths of the associations among various lipid-related indexes and clinical features consistent with atherosclerotic disease. From approximately 9,500 data sets in the overall analysis, the apolipoprotein-B/HDL cholesterol ratio emerged as the strongest correlate (odds ratio 1.177 per 1 mg/dl increment, 95% confidence interval 1.063 to 1.302, p <0.01), followed by the total or non-HDL cholesterol/HDL cholesterol ratio (odds ratio for each 1.070 per 1 mg/dl increment, 95% confidence interval 1.024 to 1.118, p <0.01), followed by the triglyceride/HDL cholesterol ratio (odds ratio 1.033 per 1 mg/dl increment, 95% confidence interval 1.011 to 1.056, p <0.01). Neither LDL cholesterol nor the LDL/HDL cholesterol ratio correlated significantly. Parallel analyses comparing tertile extremes and analyses in subgroups determined by gender, age, and body mass index revealed similar findings. The LDL/HDL cholesterol ratio was only significant for lean patients. In conclusion, these observations add to the published data suggesting that LDL cholesterol may not be the best target of lipid-lowering treatment strategies.