This paper presents a general mathematical programming model for the synthesis of distributed treatment systems for industrial effluents discharged to watersheds. In addition to addressing the economic and environmental concerns of the design, the paper introduces safety as an additional objective. A multi-objective optimization formulation is developed to simultaneously address and reconcile the various objectives. Material flow analysis (MFA) is used to track the flows and concentrations throughout the watershed system while accounting for the different sources (industrial, sanitary, agricultural, precipitation, etc.), extractions (agricultural, filtration, evaporation, etc.), and physical, biological, and chemical phenomena occurring within the watershed. Additionally, the formulation allows the installation of treatment systems for the industrial effluents. The economic, environmental, and safety aspects of these treatment units are incorporated. A case study with different scenarios for the Balsas watershed in Mexico is considered to show the applicability of the proposed approach. (C) 2013 Elsevier Ltd. All rights reserved.