Variations of the X-ray spectral slope have been found in many Active Galactic Nuclei (AGN) at moderate luminosities and redshifts, typically showing a “softer when brighter” behaviour. However, similar studies are not usually performed for high-luminosity AGNs. We present an analysis of the spectral variability based on a large sample of quasars in wide intervals of luminosity and redshift, measured at several different epochs, extracted from the fifth release of the XMM Newton Serendipitous Source Catalogue. Our analysis confirms a “softer when brighter” trend also for our sample, extending to high luminosity and redshift the general behaviour previously found. These results can be understood in light of current spectral models, such as intrinsic variations of the X-ray primary radiation, or superposition with a constant reflection component.