Water quality standards (WQSs) based on water quality measures (e.g., fecal indicator bacteria (FIB)) have been used by regulatory agencies to assess onsite, non-potable water reuse systems. A risk-based approach, based on quantitative microbial risk assessment, was developed to define treatment requirements that achieve benchmark levels of risk. This work compared these approaches using the predicted annual infection risks for non-potable reuse systems that comply with WQSs along with the benchmark risk levels achieved by the risk-based systems. The systems include a recirculating synthetic sand filter or an aerobic membrane bioreactor (MBR) combined with disinfection. The greywater MBR system had predicted risks in the range of the selected benchmark levels. However, wastewater reuse with systems that comply with WQSs had uncertain and potentially high predicted risks (i.e., >10−2 infections per person per year) in residential applications, due to exposures to viruses and protozoa. The predicted risks illustrate that WQSs based on FIB treatment performance do not ensure adequate treatment removal of viruses and protozoa. We present risk-based log10 pathogen reduction targets for intermediate-sized non-potable systems, which are 0.5 log10 less than those previously proposed for district-sized systems. Still, pathogen treatment performance data are required to better manage non-potable reuse risk.