Recent evidence indicates that water is one of the most overlooked and underestimated sources of healthcare-associated infections (HAIs). Opportunistic premise plumbing pathogens (OPPPs) are a group of natural waterborne pathogens that can persist in premise plumbing for long periods because of their unique characteristics. These include disinfectant resistance, viability inside amoeba, biofilm formation, and growth in nutrient-depleted environments. The pathogens can affect patients through various mechanisms, including direct contact, ingestion, aspiration, and aerosol inhalation. Most importantly, the transfer of pathogens between human microbiota and premise plumbing can cause hospital water systems to be reservoirs of multidrug-resistant bacteria. Biofilms formed on the outlet devices, such as tap faucets, shower heads, and sink drains provides an ideal niche for transmission of antimicrobial resistance. Contaminated wastewater systems are often sources of HAIs. A combination of interventions must be employed to manage water-related HAIs, including the general reinforcement of infection control measures, thermal and chemical disinfection, and consistent water flow.