The cost-effectiveness of total maximum daily load (TMDL) programs depends heavily on program design. We develop an optimization framework to evaluate design choices for the TMDL for the Potomac River, a Chesapeake Bay sub-basin. Scenario results suggest that policies inhibiting nutrient trading or offsets between point and nonpoint sources increase compliance costs markedly and reduce ecosystem service co-benefits relative to a least-cost solution. Key decision tradeoffs highlighted by the analysis include whether agricultural production should be exchanged for low-cost pollution abatement and other environmental benefits and whether lower compliance costs and higher co-benefits provide adequate compensation for lower certainty of water-quality outcomes.