The atropisomerism of novel 2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-oxides 1 bearing dissymmetric (ortho-substituted) 5-aryl residues and the homologous 1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxides 2 was investigated. The existence of a chiral axis was demonstrated for compound 1a by X-ray diffraction and by DFT calculations of the ground state geometry. The resolution of the atropisomeric enantiomers on chiral stationary phases is reported. The barriers to enantiomerization were determined by off-line racemization studies and/or by treatment of the plateau-shaped chromatograms during chromatography on chiral support. A clear ring size effect was evidenced. In all cases, six-membered amidine derivatives 1 showed higher barriers than the corresponding lower homologues 2, which also display lower sensitivity to the substituent size. Transition states for the interconversion of the atropisomers were located using DFT calculations, and involved the interaction of the ortho substituent with the formally sp² nitrogen in the amidine moiety. In contrast, in the most favored enantiomerization transition state of the 2-nitro derivative the ortho substituent is close to the N-oxide group.