Despite US sanitation advancements, millions of waterborne disease cases occur annually, although the precise burden of disease is not well quantified. Estimating the direct healthcare cost of specific infections would be useful in prioritizing waterborne disease prevention activities. Hospitalization and outpatient visit costs per case and total US hospitalization costs for ten waterborne diseases were calculated using large healthcare claims and hospital discharge databases. The five primarily waterborne diseases in this analysis (giardiasis, cryptosporidiosis, Legionnaires' disease, otitis externa, and non-tuberculous mycobacterial infection) were responsible for over 40 000 hospitalizations at a cost of $970 million per year, including at least $430 million in hospitalization costs for Medicaid and Medicare patients. An additional 50 000 hospitalizations for campylobacteriosis, salmonellosis, shigellosis, haemolytic uraemic syndrome, and toxoplasmosis cost $860 million annually ($390 million in payments for Medicaid and Medicare patients), a portion of which can be assumed to be due to waterborne transmission.