This paper examines the optimal allocation of several inputs in the context of seawater desalination by reverse osmosis (RO) as a source of municipal (or commercial or industrial) water. A cost-minimization model is developed, a production function is estimated, and sensitivity analyses are conducted using the optimization model to investigate the effect of environmental conditions and economic factors on the optimal input portfolio and the cost of operating a modeled seawater desalination facility. The objectives of this paper are to better understand the effect on the seawater desalination facility’s costs and input portfolio from changes in water quality, membrane lifespan, daily operations schedule, and energy prices. Findings include that lower total facility costs are associated with warm-weather water quality parameters, longer membrane life, and mid-range daily operations schedule (14.265 hours/day). Under most conditions, an interruptible power supply regime reduces facility costs. Exceptions include when the interruptible power supply regime implies significant reductions in operating hours and the associated reduction in energy price is very small.