Its has been reported that human DNA is able to stimulate toll like receptor 9 (TLR9) in B cells and plasmacytoid dendritic cells under controlled in vitro conditions. This finding is peculiar because the human genome and the immune system have co-evolved multiple mechanisms so that under physiological conditions human DNA is ignored by the immune system, whereas bacterial DNA is recognised as foreign and elicits an immune response. Given that human DNA can stimulate TLR9, and that TLR9 is preferentially stimulated by very specific CpG motifs, we hypothesised that the human genome contains immunostimulatory CpG motifs. By reviewing past literature, 47 6-base motifs were designed based on their theoretical ability to stimulate TLR9. The human genome contains 8 million such motifs although interestingly, their frequency is 22% less than what would be expected if the distribution of CpG motifs were random. Conversely, motifs that are known to either inhibit or have no effect on TLR9 are found to be over-represented in the genome. The reverse is observed in the genomes of common pathogen where the immunostimulatory motifs are found to be over-represented.