Despite the availability of several homogenous LDL-C assays, calculated Friedewald’s LDL-C equation remains the widely used formula in clinical practice. Several novel formulas developed in different populations have been reported to outperform the Friedewald formula. This study validated the existing LDL-C formulas and derived a modified LDL-C formula specific to a Ghanaian population. In this comparative study, we recruited 1518 participants, derived a new modified Friedewald’s LDL-C (M-LDL-C) equation, evaluated LDL-C by Friedewald’s formula (F-LDL-C), Martin’s formula (N-LDL-C), Anandaraja’s formula (A-LDL-C), and compared them to direct measurement of LDL-C (D-LDL-C). The mean D-LDL-C (2.47±0.71 mmol/L) was significantly lower compared to F-LDL-C (2.76±1.05 mmol/L), N-LDL-C (2.74±1.04 mmol/L), A-LDL-C (2.99±1.02 mmol/L), and M-LDL-C (2.97±1.08 mmol/L) p < 0.001. There was a significantly positive correlation between D-LDL-C and A-LDL-C (r=0.658, p