Most modern semiempirical quantum‐chemical (SQC) methods are based on the neglect of diatomic differential overlap (NDDO) approximation to ab initio molecular integrals. Here, we check the validity of this approximation by computing all relevant integrals for 32 typical organic molecules using Gaussian‐type orbitals and various basis sets (from valence‐only minimal to all‐electron triple‐ζ basis sets) covering in total more than 15.6 million one‐electron (1‐e) and 10.3 billion two‐electron (2‐e) integrals. The integrals are calculated in the nonorthogonal atomic basis and then transformed by symmetric orthogonalization to the Löwdin basis. In the case of the 1‐e integrals, we find strong orthogonalization effects that need to be included in SQC models, for example, by strategies such as those adopted in the available OMx methods. For the valence‐only minimal basis, we confirm that the 2‐e Coulomb integrals in the Löwdin basis are quantitatively close to their counterparts in the atomic basis and that the 2‐e exchange integrals can be safely neglected in line with the NDDO approximation. For larger all‐electron basis sets, there are strong multishell orthogonalization effects that lead to more irregular patterns in the transformed 2‐e integrals and thus cast doubt on the validity of the NDDO approximation for extended basis sets. Focusing on the valence‐only minimal basis, we find that some of the NDDO‐neglected integrals are reduced but remain sizable after the transformation to the Löwdin basis; this is true for the two‐center 2‐e hybrid integrals, the three‐center 1‐e nuclear attraction integrals, and the corresponding three‐center 2‐e hybrid integrals. We consider a scheme with a valence‐only minimal basis that includes such terms as a possible strategy to go beyond the NDDO integral approximation in attempts to improve SQC methods. © 2018 Wiley Periodicals, Inc. The evaluation of 2‐e integrals in the nonorthogonal atomic basis ({ϕ i}) dominates the computational cost of ab initio Hartree–Fock calculations. We demonstrate that both the 1‐e and 2‐e integrals in the molecular Hamiltonian are reduced significantly in the Löwdin basis ({ϕ¯ u})(ϕ¯μ), albeit to different extent for different types of integrals. Based on our analysis, we consider the novel NAX scheme (Neglect of Atomic eXchange) for molecular integrals that goes beyond the semiempirical NDDO approximation.