By testing a large number of ONIOM (our own N-layered integrated molecular orbital + molecular mechanics) combinations against the standard complete active space self-consistent field (CASSCF) method with the 6-31G(d) basis set, we have investigated the suitability of the ONIOM (molecular orbital + molecular orbital) method for the investigation of the first singlet excited state (S-1) photoisomerization pathways in protonated Schiff bases (PSBs). For the isomerization reaction of an 11-nonhydrogen (H) PSB (10-non-H Schiff base plus one methyl group), ONIOM can accurately reproduce the standard CASSCF(10e/10o) (10 active electrons in 10 orbitals) results for only 10% of the computer time. The model system, which includes the protonated Schiff base group as well as the isomerization bond, was always treated at the CASSCF level. With the unrestricted Hartree-Fock first triplet state (T-1) in the low level, the S-1 energy profile is reproduced accurately, while time-dependent Hartree-Fock or single excitation configuration interaction in the low level reproduces the difference between the singlet ground state (S-0) and S-1 states very well. Using our ONIOM method, we also computed the first S-1 isomerization energy profile of the entire retinal protonated Schiff base.