Highly sensitive and selective detection of heavy metal ions, such as Hg2+, is of great importance because the contamination of heavy metal ions has been a serious threat to human health. Herein, we have developed poly-cytosine (polyC)-mediated surface-enhanced Raman scattering (SERS) nanotags as a sensor system for rapid, selective, and sensitive detection of Hg2+ based on thymidine-Hg2+-thymidine (T-Hg2+-T) coordination and polyC-mediated Raman activity. The SERS nanotags exploit the mismatched T-T base pairs to capture Hg2+ form T-Hg2+-T bridges, which induce the aggregation of nanotags giving rise to the drastic amplification in the SERS signals. Moreover, this polyC not only provides the anchoring function to induce the formation of intrinsic silver-cytosine coordination but also engineers the Raman-activity of SERS nanotags by mediating its length. As a result, the polyC-mediated SERS nanotags show an excellent response for Hg2+ in the concentration range from 0.1 to 1000 nM and good selectivity over other metal ions. Given its simple principle and easy operation, the polyC-mediated SERS nanotags, therefore, could serve as a promising sensor for practical use.