A multiscale mixed finite element method (MsMFEM) is analyzed and further developed. It has been applied to simulate two-phase flows in strongly heterogeneous porous media. The method is a variant of that one introduced by Z. Chen and T. Y. Hou [Math. Comput. 72, No. 242, 541–576 (2003; Zbl 1017.65088)], and is also closely related to the subgrid upscaling introduced by T. Arbogast [SIAM J. Numer. Anal. 42, No. 2, 576–598 (2004; Zbl 1078.65092)]. The main idea behind the MsMFEM is to model fine-scale patterns in the velocity field by computing special finite element basis functions which reflect the impact of fine-scale heterogeneous structures. In the two-grid approach, the pressure equation is solved on a coarse grid using locally defined basis functions which are computed numerically by solving flow problems on an underlying fine grid. The main objectives of this paper are to extend the hierarchical multiscale method (MsMFEM) to nonuniform and unstructured coarse grids, to identify in which situations the method suffers from loss of accuracy, to select criteria which detect the problems and to propose efficient remedies based on nonuniform coarsening. The suggested strategies are illustrated in several numerical experiments.