For interaction energies, larger system sizes equate to larger errors in DFT, even after accounting for uncertainty in the benchmarks. All of the large-system DFT calculations reported in this work were performed basis sets no smaller than def2-TZVPD or aug-cc-pVTZ, and many of them with def2-QZVPD, and Boys-Bernardi CP correction was used in every case. These interaction energies ought to lie close to the DFT/CBS limit. The magnitude of the BSSE grows with system size and in vdW complexes with 100 atoms, DFT/double-ζ interaction energies may err by 10-50 kcal/mol or more, simply due to BSSE, unless CP correction is applied; see Table . Additional large-system examples are provided in Fig. , illustrating how CP-corrected and uncorrected interaction energies converge to the CBS limit for large protein-ligand complexes. Two of these examples involve small ligands (benzene and phenol) while two others contain larger ligands: 81 atoms for RU85052 and 92 atoms for indinavir. In all four cases, the protein model is large by quantum chemistry standards, up to 235 atoms, and these tests are part of ongoing efforts to obtain quantum-chemical results for enzymes that are converged with respect to the size of the model system. There is a tendency to avoid diffuse basis functions in large DFT calculations, as they dramatically increase the cost by hampering integral screening, and may slow SCF convergence due to linear dependencies unless very tight thresholds are used. For the protein-phenol and proteinbenzene complexes in Fig. (a) and Fig. ), calculations at the M06-2X/def2-SVP level en-gender ≈ 6 kcal/mol of BSSE, as measured by the magnitude of the CP correction, but for the indinavir@1HSG complex in Fig. (d) that difference is more than 40 kcal/mol! These differences persist even when diffuse functions are added, yet adding a single set of diffuse functions, in combination with CP corrections, significantly improves each of the ligand-protein interaction energies in Fig. , and M06-2X(CP)/def2-SVPD results are within 1 kcal/mol of M06-2X/CBS values. In the absence of CP correction, that level of convergence is not reached for the large-ligand systems unless the def2-TZVPD basis set is used. As such, CP correction should be considered mandatory in all noncovalent calculations that use Gaussian basis sets.