The objective of this analysis was to demonstrate the frequency and extent of error that results from using the TC/HDL C ratio rather than the apoB/apoA-I ratio to estimate the lipoprotein-related risk of vascular disease within 94,667 men and 75,675 women in the Apoprotein-related Mortality Risk (AMORIS) cohort. The odds ratio (OR) for the risk of fatal myocardial infarction was determined for 1 SD change in the apoB/apoA-I ratio and all the conventional cholesterol ratios--TC/HDL C ratio, LDL C/HDL C ratio, non-HDL C/HDL C ratio. In both men and women, the apoB/apoA-I ratio was significantly greater than any of the cholesterol ratios, which, in fact, differed little. Therefore, the apoB/apoA-I ratio was taken as the most accurate index of the lipoprotein-related risk of vascular disease. Using Receiver Operating Characteristic analysis, it was demonstrated that the diagnostic accuracy of the apoB/apoA-I ratio was significantly greater than any cholesterol ratio in those with an LDL cholesterol <3.6 mmol L(-1) compared to those with an LDL cholesterol >3.6 mmol L(-1). Indeed, the difference between the apoB/apoA-I OR compared with the TC/HDL C OR progressively widened as risk increased. This suggests that the advantage of the apoB/apoA-I ratio is greatest in the population at highest risk. The distribution of subjects by quintiles showed in both genders that whilst agreement was greatest at the extremes, even at these points there was substantial discordance between the TC/HDL C and the apoB/apoA-I ratios. Within the middle of the distribution, less than 50% of the values were concordant. Finally, when comparing the ORs, the TC/HDL C ratio underestimated risk in 69.4% of male subjects and overestimated risk in 26.1% of male subjects, whereas in the female subjects, the TC/HDL C ratio underestimated risk in 84.9% of the subjects and overestimated risk in 12.0%. Thus, using the conventional cholesterol ratios rather than the apoB/apoA-I ratio results in frequent and substantial error in the estimation of the lipoprotein-related risk of vascular disease.