Cross second virial coefficients B12 are only a function of temperature and do, therefore, not depend on the composition of the mixture. However, many commonly used mixture models do not fulfill this condition. In this work, we compare the results of multifluid mixture models for B12 with accurate experimental data for mixtures of methane + propane, argon + carbon dioxide, hydrogen + carbon dioxide, and ethane + carbon dioxide. It was found that neither multifluid mixture models with adjusted parameters nor multifluid mixture models employing a theoretically based departure function using either UNIFAC or COSMO-SAC as the gE-model are capable of describing B12 correctly. Furthermore, the ability of other commonly used equations of state (SRK, PSRK, and PCP-SAFT) to correctly represent cross second virial coefficients is evaluated and the results of these equations of state are used for comparison. A possible modification of the multifluid mixture model in the limit of zero density for achieving the correct behavior of the cross second virial coefficient is discussed.