6-Substituted pyrrolo-dC-pyrrolo-dC mismatches selectively capture silver ions to form extraordinarily stable metal-mediated base pairs. One single modification in a 12-mer duplex causes a Tm increase of 36.0 °C relative to the metal-free mismatched duplex. Spectrophotometric titrations as well as ESI mass spectra confirmed the binding of two silver ions per base pair. The Ag(+)-mediated base pairs may permit the construction of metal-responsive DNA with a very high silver loading.