Methylmercury (CH3Hg(+)), the common organic source of mercury, is well-known as one of the most toxic compounds that is more toxic than inorganic or elemental mercury. In seabeds, the deposited Hg(2+) ions are converted into CH3Hg(+) by bacteria, where they are subsequently consumed and bioaccumulated in the tissue of fish, and finally, to enter the human diet, causing severe health problems. Therefore, sensitive and selective detection of bioaccumulation of CH3Hg(+) in fish samples is desirable. However, selective assay of CH3Hg(+) in the mercury-containing samples has been seriously hampered by the difficulty to distinguish CH3Hg(+) from ionic mercury. We report here that metal amalgamation, a natural phenomenon occurring between mercury atoms and certain metal atoms, combining with DNA-protected silver nanoparticles, can be used to detect CH3Hg(+) with high sensitivity and superior selectivity over Hg(2+) and other heavy metals. In our proposed approach, discrimination between CH3Hg(+) and Hg(2+) ions was realized by forming Ag/Hg amalgam with a CH3Hg(+)-specific scaffold. We have found that Ag/Hg amalgam can be formed on a CH3Hg(+)-specific DNA template between silver atoms and mercury atoms but cannot between silver atoms and CH3Hg(+). With a dye-labeled DNA strand, the sensor can detect CH3Hg(+) down to the picomolar level, which is >125-fold sensitive over Hg(2+). Moreover, the presence of 50-fold Hg(2+) and 10(6)-fold other metal ions do not interfere with the CH3Hg(+) detection. The results shown herein have important implications for the fast, easy, and selective detection and monitoring of CH3Hg(+) in environmental and biological samples.