Mammalian genomes, unlike the genomes of Drosophila and yeast, are characterized by CpG methylation and concomitant CpG depletion, which is caused by the enhanced mutation rate of 5-methylcytosine. To find out whether local nucleotide sequences around existing methylated CpG dinucleotides have common patterns, we analyzed a large population of CpG-poor regions in human DNA, which are typically methylated. We detected a novel periodic variation in the numbers of purine bases around CpGs in the noncoding parts of these sequences. This periodicity of eight nucleotides gradually diminished over 64 nucleotides on each side of the central CpG. Furthermore, the frequencies of the 5' and 3' nearest neighbors of CpGs in CpG-poor regions were biased towards cytosine and guanine, respectively. Such biased sequence contexts may have helped to stabilize CpGs against depletion during mammalian evolution.