Abstract: Mefenamic acid is a NSAID that is widely used in analgesia. However, its use has been implicated in several cases of nephrotoxicity including acute renal failure and tubulointestinal nephritis. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MFA and its metabolites have similar LUMO-HOMO energy differences except MFA-Glu which has a much smaller value. This means that MFA and its metabolites have similar kinetic lability except MFA-Glu which is much more labile. The high kinetic lability of MFA-Glu suggests that it may react with biomolecules such as intra- and extracellular proteins more readily. However, whether this binding manifests itself as being a cause of MFA-induced toxicity remains unclear and may be confusing since the acyl glucuronides are considered to be less toxic. It may be that the formation of acyl glucuronide reduces toxicity associated with the carboxylic group but introduces new ones due to its high reactivity. It is found that the metabolites if MFA have higher solvation energies than MFA so that they may be more readily excreted in the urine.