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Mandelic acid (MA) is generally used as a biomarker of the exposure to styrene, and is also used as a urinary antiseptic in clinic and an important chiral intermediate in pharmaceutical industry.In the present study, two isozymes of rat long chain S-2-hydroxy acid oxidase 2 (rHAO2), rHAO2 β1 and β2, were firstly recombinant expressed, and then their metabolic profiles to S-MA and its analogue S-2-chloromandelic acid (S-ClMA) were studied.rHAO2 β1 and β2 showed similar kinetic profiles for both S-MA and S-ClMA, whereas S-MA and S-ClMA showed significant differences in their kinetic profiles.The Km and kcat values of S-MA were about 2 and 10-fold of that of S-ClMA, respectively.Based on the crystal structure of rHA02, theoretical computations were further carried out to get a better understanding of structural mechanism for HAO2-promoted metabolism of S-MA and S-ClMA.MD simulations and binding free energy analyses predicted that S-ClMA binds more tightly with rHAO2 than S-MA.