Potable reuse requires a multiple barrier approach to control pathogens from a grossly contaminated source. The primary multiple pathogen barriers used at the Denver Potable Water Reuse Demonstration Plant are excess lime treatment, ozonation, reverse osmosis, and chlorine dioxide. Undisinfected secondary wastewater effluent is subjected to high-pH lime treatment which inactivates viruses and bacteria, reduces TOC, removes suspended solids, and precipitates heavy metals and phosphorus. Ozone is an effective virucide and bactericide and chemically oxidizes refractory organics. Reverse osmosis is a physical barrier to pathogens and removes ions, certain organics, and nitrogen forms. Chlorine dioxide provides a persistent residual and minimizes the potential for chloro-organic formation. Operational experience is described and disinfection performance evaluated.