Chiral separations of a series of 15 pyrrolidin-2-ones on polysaccharide stationary phases in the HPLC system have been reported. Three stationary phases have been applied: Chiralpak AD, Chiralpak IA and Chiralcel OD. The changes of retention and enantioselectivity have been examined depending on the organic modifier (ethanol or 2-propanol). The addition of a small amount of water has also been studied. Amylose columns exhibit better enantioselectivity (higher alpha values) than cellulose ones. All compounds can be enantiomerically separated on a Chiralpak IA column with EtOH as the organic modifier. The separation of all compounds on a Chiralpak AD and Chiralcel OD columns required changes of mobile phase composition. Depending on the structure of the compounds, the type of stationary phase, as well as the composition of the mobile phase, different intermolecular interactions can play a key role in chiral discrimination.