Many important physical, chemical, and biological processes taking place in nanoscopic confined water environments may behave very different from that in bulk. In this paper, we report an unusual nonenzymatic degradation of DNA molecules in the confined water nanofilm on mica substrate. We found that the half-time of DNA in the degradation process in the water nanofilm is about several hours under high RH at temperatures ranging from 10 to 50 °C, which is much faster than that in bulk water, ∼10(11) years at 25 °C. Careful analysis indicated that it was the formation of a water/vapor interface in the water nanofilm that played a major role in promoting DNA degradation.