In this work, we investigated the effects of carboxybetaine (CB) and (ethylene glycol)(4) (EG(4)) solutes on chymotrypsin inhibitor 2 (CI2) as a model protein using molecular dynamics simulations. The properties studied include the radial distribution functions of these two solutes to the C-α atoms of the 64 residues of CI2, the average numbers of solute-protein and water-protein hydrogen bonds, the root mean square deviation of the C-α atoms of the protein, and the solvent access surface area of the protein. Results show that these two solutes share some common properties while have some different effects on the protein. Both of these two solutes do not accumulate preferentially near the protein and CI2 is folded with either of them. However, CI2 is found to have properties in the CB solution closer to bulk water, whereas CI2 shows reduced flexibility and decreased SASA of the hydrophobic domain in the EG(4) solution. Although the protein is folded with both CB and EG(4), superhydrophilic CB has a minimal effect on the protein due to the shared zwitterionic nature of both CB and protein whereas amphiphilic EG(4) alters the properties of the protein via hydrophobic interactions.