We develop an empirically constrained multicompartment box model for mercury cycling in open ocean regions to investigate changes in concentrations resulting from anthropogenic perturbations of the global mercury cycle. Using Monte Carlo simulations, we explicitly consider the effects of variability in measured parameters on modeled seawater concentrations. Our simulations show that anthropogenic enrichment in all surface (25%) and deep ocean waters (11%) is lower than global atmospheric enrichment (300–500%) and varies considerably among geographic regions, ranging from >60% in parts of the Atlantic and Mediterranean to <1% in the deep Pacific. Model results indicate that open ocean mercury concentrations do not rapidly equilibrate with atmospheric deposition and on average will increase if anthropogenic emissions remain at their present level. We estimate the temporal lag between changes in atmospheric deposition and ocean mercury concentrations will vary from decades in most of the Atlantic up to centuries in parts of the Pacific.