Microbial conversion of inorganic mercury [Hg(II)] to organometallic methylmercury (MeHg) is a global concern because MeHg is a neurotoxin and can bioaccumulate and biomagnify to high levels. Here we use Desulfovibrio desulfuricans ND132 as a model bacterium to examine the roles of divalent metal ions on Hg(II) uptake and methylation. The presence of a small amount of copper ions [Cu(II), <100 nM] enhances Hg(II) uptake and methylation by washed cells of ND132, while Hg(II) methylation is inhibited at higher Cu(II) concentrations due to copper toxicity to the microorganism. The enhancement or inhibitory effect of Cu(II) is both time and Cu concentration dependent: The presence of nanomolar concentrations of Cu(II) facilitates rapid uptake of Hg(II) (within minutes) and doubles MeHg production within a 24 h period, but micromolar concentrations of Cu(II) completely inhibit Hg(II) methylation. The Cu(II)-enhanced Hg(II) uptake and methylation are highly specific and not observed with divalent metal ions such as Zn(II), Ni(II), Mg(II), and Mn(II) under the same experimental conditions. These observations suggest a synergistic effect of Cu(II) on Hg(II) uptake and methylation, possibly facilitated by copper transporters or metallochaperones in this organism, and highlight that complex environmental factors affect MeHg production in the environment.