A simulation/optimization model is developed to demonstrate the need for inclusion of interactive pollutant effects in multiple-pollutant wastewater management, by comparing single- and multiple-pollutant least cost approaches that maintain downstream ambient quality levels. The model chooses biological oxygen demand (BOD), N, and P abatement levels for point sources that minimize the combined wastewater treatment costs of the pollutants in order to achieve chosen ambient quality standards. Nonlinear pollutant interactions result in a nonlinear Jacobian matrix of marginal water quality impacts, creating a nonlinear constraint set. The Jacobian is iteratively updated by the simulation model using iterative solutions from the optimization model. The open modeling framework allows other types of programming problems to be solved as well, such as mixed integer and mixed integer nonlinear problems. Single-and multiple-pollutant management approaches are applied to a case study of the Nitra River Basin in Slovakia. The regrets resulting from implementing BOD-only or fixed Jacobian solutions are shown, and the robustness of the solution procedure is demonstrated by varying the initial pollution abatement levels. ¿ 2000 American Geophysical Union