A QM/QM approach incorporating the correlation consistent composite approach (ccCA) into the ONIOM multilayer methodology has been implemented. This new multilayer composite scheme, ONIOM-ccCA, enables the accurate prediction of thermochemical properties for systems containing dozens and potentially hundreds-of atoms. ONIOM-ccCA is used to predict the C-H bond dissociation energies of 18 anthracene and fiuorene analogues, containing up to 43 atoms, to within 1.2 kcal mol(-1) of experimental values. Several density functional and basis set combinations are evaluated for use as the low level QM layer. The mean absolute deviation (1.2 kcal mol(-1)) using the most accurate ONIOM-ccCA method, ccCA:B3LYP/cc-pVTZ, is significantly lower than that of an earlier reported multilayer composite scheme [2.4 kcal mol(-1), Li, M.-J.; Liu, L.; Fu, Y.; Guo, Q.-X. J. Phys. Chem. B, 2005, 109, 13818]. Thus, through use of ONIOM-ccCA, accurate thermochemical calculations are now feasible for sizable molecular systems of chemical or biological interest.