Microbial contamination of drinking water post-municipal treatment is difficult to predict as a risk factor for human health. One method to reduce morbidity or mortality from unpredictable exposures is through point-of-use (POU) treatment devices. The goal of this project was to assess the cost-benefit of POU water treatment at the tap in terms of protection from microbes in drinking water. This project estimated: (1) incidence of acute illness (AI), sequela, and mortality associated with waterborne pathogens; (2) illness reduction rates from using POU devices; and (3) healthcare cost reductions associated with POU devices. Infection rates and costs associated with 10 of the most common waterborne pathogens were identified and used to calculate national annual costs. We estimated 9M AI, 0.6M sequela, and 1,400 mortality cases that occur annually in the USA from these pathogens. The greatest cost-benefit was seen when considering the totality of disease burden reduction (AI, sequela, and mortality) including all pathogens at a national level and applying a 35% infection reduction, resulting in a total cost per averted disease case of $1,815. This study suggests that it is cost-beneficial to prevent water-related illness using POU devices.