We estimated the disease burden from water, sanitation, and hygiene at the global level taking into account various disease outcomes, principally diarrheal diseases. The disability-adjusted life year (DALY) combines the burden from death and disability in a single index and permits the comparison of the burden from water, sanitation, and hygiene with the burden from other risk factors or diseases. We divided the world's population into typical exposure scenarios for 14 geographical regions. We then matched these scenarios with relative risk information obtained mainly from intervention studies. We estimated the disease burden from water, sanitation, and hygiene to be 4.0% of all deaths and 5.7% of the total disease burden (in DALYs) occurring worldwide, taking into account diarrheal diseases, schistosomiasis, trachoma, ascariasis, trichuriasis, and hookworm disease. Because we based these estimates mainly on intervention studies, this burden is largely preventable. Other water- and sanitation-related diseases remain to be evaluated. This preliminary estimation of the global disease burden caused by water, sanitation, and hygiene provides a basic model that could be further refined for national or regional assessments. This significant and avoidable burden suggests that it should be a priority for public health policy.