Eleven polysaccharide-based chiral stationary phases were screened to separate stereoisomers of six lactam derivatives by supercritical fluid chromatography (SFC). Those molecules are antagonists of the P2×7 receptor with potential anti-inflammatory activity. They present a mixture of either two enantiomers, or four or eight stereoisomers depending on the number of chiral centers in their structure. The effect of chiral stationary phase, either amylose-or cellulose-based, coated or immobilized, chlorinated or non-chlorinated, on retention and selectivity of those compounds was studied. The effect of the co-solvent nature (methanol, ethanol, propan-2-ol and acetonitrile) and percentage (15 to 40 %), temperature (20 to 45 • C) and backpressure (8 to 20 MPa) on the enantioseparation and retention of 1-(2-chlorobenzyl)-5-((4-methoxyphenyl)amino)pyrrolidin-2-one (compound 4) was thoroughly studied. Thus, optimal conditions were defined for each derivative in order to implement the preparative separation of the whole series, except of 1-((3,4-dimethoxyphenyl)(phenyl)methyl)-5-oxo-N-(1phenylethyl)pyrrolidine-2-carboxamide) (compound 6) for which none of the eleven columns could resolve the eight stereoisomers. The small-scale preparative separation of the enantiomers of the most promising derivative, i.e. 3-acetyl-1-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-5-oxopyrrolidine-2-carboxamide (compound 2), is presented.