The tendency of individual CpG sites to be methylated is distinctive, non-random and well-regulated throughout the genome. We investigated the structural and spatial factors influencing CpGs methylation by performing an ultra-deep targeted methylation analysis on human, mouse and zebrafish genes. We found that methylation is not a random process and that closer neighboring CpG sites are more likely to share the same methylation status. Moreover, if the distance between CpGs increases, the degree of co-methylation decreases. We set up a simulation model to analyze the contribution of both the intrinsic susceptibility and the distance effect on the probability of a CpG to be methylated. Our finding suggests that the establishment of a specific methylation pattern follows a universal rule that must take into account of the synergistic and dynamic interplay of these two main factors: the intrinsic methylation susceptibility of specific CpG and the nucleotide distance between two CpG sites. •The methylation of CpGs occurs in a non-stochastic manner.•Some CpG sites are more prone to be methylated than others.•Closer CpG sites are more likely to be co-methylated.•The degree of co-methylation decreases as the distance between CpG sites increases.