Effect of polyethylene glycol (PEG) on protein solubility has been primarily ascribed to its large hydrodynamic size and thereby molecular crowding effect. However, PEG also shows characteristics of organic solvents. Here, we have examined the solubility of glycine and aliphatic and aromatic amino acids in PEG solutions. PEG400, PEG4000, and PEG20000 decreased the solubility of glycine, though to a much smaller magnitude than the level achieved by typical organic solvents, including ethanol and dimethyl sulfoxide. PEG4000 showed varying degree of interactions with amino acid side chains. The free energy of aliphatic side chains marginally increased by the addition of PEG4000, indicating their weak unfavorable interactions. However, it significantly decreased the free energy of the aromatic side chains and hence stabilized them. Thus, it was concluded that PEG behaves like weak organic solvents; namely PEG destabilized (interacted unfavorably with) polar and charged groups and stabilized (interacted favorably with) aromatic groups. Interestingly, the interaction of PEG20000, but neither PEG400 nor PEG4000, with glycine resulted in phase separation under the saturated concentration of glycine. © 2011 Wiley Periodicals, Inc. Biopolymers 97: 117–122, 2012.