Background. Promoter methylation is associated with gene repression; however, little is known about its mechanism. It was proposed that the repression of methylated genes is achieved through the recruitment of methyl binding proteins (MBPs) that participate in closing the chromatin. An alternative mechanism suggests that methylation interferes with the binding of either site specific activators or more general activators that bind to the CpG dinucleotide. However, the relative contribution of these two mechanisms to gene repression is not known. Results. Bioinformatics analyses of genome-wide transcriptome and methylome data support the latter hypothesis by demonstrating a strong association between transcription and the number of unmethylated CpGs at the promoter of genes lacking CpG islands. Conclusions. Our results suggest that methylation represses gene expression mainly by preventing the binding of CpG binding activators.