Murid nuclear genomes are more homogeneous in GC content than those of most mammals, which leads to the question of how such important compositional changes have accumulated. This paper reports on relationships between frequencies of synonymous differences and GC change, in the lineages leading to human and murids. For this, we used the four-species approach: GC changes between human and murids were compared to the frequencies of synonymous differences, measured between two independent species without GC change (bovine and pig), by using orthologous genes common to all four species. We report three conclusions: (1) Among genes with little GC change, 60% of the variability of synonymous substitution frequencies is explained by the gene-specific rate component. (2) GC changes in murid genomes are independent of the gene-specific rate component. Slowly evolving genes in pig bovine comparison can show strong GC change in murids. (3) By using a GC-independent estimate of the substitution rate, we show that GC changes in murid genomes increase synonymous substitution frequencies. The GC homogenization considerably weakens the gene-specific conservation of substitution rates in murids, and could explain part of the increase of evolutionary rates observed in this group. We present a mechanism that can account for the evolution of the GC homogenization in murids.