We used quantitative microbial risk assessment (QMRA) to estimate the microbial risks from two contamination pathways in onsite non-potable water systems (ONWS): contamination of potable water by (treated) reclaimed, non-potable water and contamination of reclaimed, non-potable water by wastewater or greywater. A range of system sizes, event durations, fraction of users exposed, and intrusion dilutions were considered (chlorine residual disinfection was not included). The predicted annual microbial infection risk from domestic, non-potable reuse remained below the selected benchmark given isolated, short-duration intrusion (i.e., 5-day) events of reclaimed water in potable water. Whereas, intrusions of wastewater into reclaimed, non-potable water resulted in unacceptable annual risk without large dilutions or pathogen inactivation. We predicted that 1 user out of 10,000 could be exposed to a 5-day contamination event of undiluted wastewater in the reclaimed, non-potable water system each year to meet the annual benchmark risk of 10-4 infections per person per year; whereas, 1 user out of 1000 could be exposed to a 5-day contamination event of undiluted reclaimed water in the potable water each year. Overall, the predicted annual risks support the use of previously derived non-potable reuse treatment requirements for a variety of ONWS sizes and support the prioritization of protective measures to prevent the intrusion of wastewater into domestic ONWS.