Low or negative pressure transients in water distribution systems, caused by unexpected events (e.g. power outages) or routine operation/maintenance activities, are usually brief and thus are rarely monitored or alarmed. Previous studies have shown connections between negative pressure events in water distribution systems and potential public health consequences. Using a quantitative microbial risk assessment (QMRA) model previously developed, various factors driving the risk of viral infection from intrusion were evaluated, including virus concentrations external to the distribution system, maintenance of a disinfectant residual, leak orifice sizes, the duration and the number of nodes drawing negative pressures. The most sensitive factors were the duration and the number of nodes drawing negative pressures, indicating that mitigation practices should be targeted to alleviate the severity of low/negative pressure transients. Maintaining a free chlorine residual of 0.2 mg/L or above is the last defense against the risk of viral infection due to negative pressure transients. Maintaining a chloramine residual did not appear to significantly reduce the risk. The effectiveness of ensuring separation distances from sewer mains to reduce the risk of infection may be system-specific. Leak detection/repair and cross-connection control should be prioritized in areas vulnerable to negative pressure transients.