A series of coarse-grained models, with different levels of structural resolution, were tested to calculate the steric contributions to protein osmotic second virial coefficients (B-22,B-S) for proteins ranging from small single-domain molecules to large multidomain molecules, using the recently developed Mayer sampling method. B-22,B-S was compared for different levels of coarse-graining: four-beads-per-amino-acid (4bAA), one-bead-per-amino-acid (1bAA), one-sphere-per-domain (1sD), and one-sphere-per-protein (1sP). Values for the 1bAA and 4bAA models were quantitatively indistinguishable for both spherical and nonspherical proteins, and the agreement with values from all-atom models improved with increasing protein size, making the CG approach attractive for large proteins of biotechnological interest. Interestingly, in the absence of detailed structural information, the hydrodynamic radius (R-h) along with a simple 1sP approximation provided reasonably accurate values for B-22,B-S for both globular and highly asymmetric protein structures, while other 1sP approximations gave poorer agreement; this helps to justify the currently empirical practice of estimating B-22,B-S from R-h for large proteins such as antibodies. The results also indicate that either 1bAA or 4bAA CG models may be good starting points for incorporating short-range attractions. Comparison of gD-crystallin B-22 values including both sterics and short-range attractions shows that 1bAA and 4bAA models give equivalent results when properly scaled to account for differences in the number of surface beads in the two CG descriptions. This provides a basis for future work that will also incorporate long-ranged electrostatic attractions and repulsions.