Aggressive low-density lipoprotein cholesterol (LDL-C)-lowering strategies are recommended for prevention of cardiovascular events in high-risk populations. Guidelines recommend a 30% to 50% reduction in at-risk patients even when LDL-C concentrations are between 70 and 130mg/dl (1.8 to 3.4mmol/L). However, calculation of LDL-C by the Friedewald equation is the primary laboratory method for routine LDL-C measurement. We compared the accuracy and reproducibility of calculated LDL-C <130mg/dl (3.4mmol/L) to LDL-C measured by β quantification (considered the gold standard method) in 15,917 patients with fasting triglyceride concentrations <400mg/dl (4.5mmol/L). Both variation and bias of calculated LDL-C increased at lower values of measured LDL-C. The 95% confidence intervals for a calculated LDL-C of 70mg/dl (1.8mmol/L) and 30mg/dl (0.8mmol/L) were 60 to 86mg/dl (1.6 to 2.2mmol/L) and 24 to 60mg/dl (0.6 to 1.6mmol/L), respectively. Previous recommendations have emphasized the requirement for a fasting sample with triglycerides <400mg/dl (4.5mmol/L) to calculate LDL-C by the Friedewald equation. However, no recommendations have addressed the appropriate lower reportable limit for calculated LDL-C. In conclusion, calculated LDL-C <30mg/dl (0.8mmol/L) should not be reported because of significant deviation from the gold standard measured LDL-C results, and caution is advised when using calculated LDL-CF values <70mg/dl (1.8mmol/L) to make treatment decisions.