SimpleTreat has become a common tool used in ecological risk assessments to estimate the removal efficiency of a chemical from a secondary wastewater treatment plant and hence inform on release to the environment. Organization A, Organization B, and Organization C performed a comparative study of SimpleTreat predictions and parameter selection methodologies across the three organizations. SimpleTreat versions 3.1 and 4.1 were run for a set of 10 chemicals using different settings and different approaches to obtain the inputs needed to run the tool. The impacts of these differences on removal predictions for the set of chemicals were explored, and a unified framework was proposed to guide users in the effective use of SimpleTreat.