A two-dimensional reservoir toxics model is essential to establishing effective water resources management and protection. In a reservoir, the fate of a toxic chemical is closely connected with flow regimes and circulation patterns. To better understand the kinetic processes and persistence and predict the dissipation of toxic contaminants in the reservoir during a spill or storm runoff event, a toxics submodel was developed and incorporated into an existing laterally integrated hydrodynamics and transport model. The toxics submodel describes the physical, chemical, and biological processes and predicts unsteady vertical and longitudinal distributions of a toxic chemical. The two-dimensional toxicant simulation model was applied to Shasta Reservoir in California to simulate the physico-chemical processes and fate of a volatile toxic compound, methyl isothiocyanate (MITC), during a chemical spill into the Sacramento River in 1991. The predicted MITC concentrations were compared with those observed. The effect of reservoir flow regimes on the transport and fate of the toxic substance was investigated. The results suggested that the persistence of MITC is significantly influenced by different flow regimes. Methyl isothiocyanate is more persistent in the reservoir under an interflow condition due to reduced volatilization from deep layers than under an overflow condition. In the overflow situation, the plume moved more slowly toward the dam and experienced greater dissipation. This analysis can assist in toxic spill control and reservoir management, including field sampling and closure of water intakes.