In this paper, the advantages of using a pyridinium and imidazolium ionic liquids in the first column for GC × GC separation of complex mixtures—coal pyrolysis product, bio-oil, and essential oil from Pituranthos scoparius—in comparison with polyethylenglycol phase has been demonstrated. The nearest neighbor distance (NND) approach to evaluate the separation quality and orthogonality has been used for the comparison of GC × GC separations for different ionic liquid columns in the first dimension. It was found that they give essentially different results for both the separation quality and orthogonality, evaluated using parameters derived from NND approach. For a mixture of coal pyrolysis products containing only two classes of compounds—phenols and aromatic compounds—the most polar ionic liquid bis4MPyC6 shows nearly the highest orthogonality and separation quality. In the case of separation bio-oil and essential oil, the best orthogonality was demonstrated for the least polar of the tested ionic liquids—bis3.5MPyC9. At the same time, the efficiency of columns exerts a significant effect on the separation quality parameter. As a result, this parameter has the highest value for all mixtures tested using the polyethylene glycol (ZB-WAX) reference phase, which is the less polar from all series, but the most efficient.