Recent interest in biodiesel combustion urges the need for the theoretical chemical kinetics of large alkyl ester molecules. This is, however, computationally challenging for prevalent high-level electronic structure theory based methods. The hydrogen abstraction reactions of alky esters CnH2n+1COOCmH2m+1 (n = 1-5, 9, 15; m = 1, 2) by a hydrogen radical were investigated by a computational technique based on a two-layer ONIOM method, employing a QCISD(T)/CBS method for the high layer and a DFT method for the low layer. The calculated energy barriers and heats of reaction, using the ONIOM method with a minimum of the required chemically active portion, are in very good agreement with those obtained using the widely accepted high-level QCISD(T)/CBS theory because the computational errors were less than 0.1 kcal mol(-1) for all the tested cases. The ONIOM[QCISD(T)/CBS:DFT] method provides a computationally accurate and affordable approach to the high-level theoretical chemical kinetics of large biodiesel molecules.