Abstract Water soluble compounds persistent in humans and the environment pose a challenge for estimating safe levels in tap water. A viable approach to estimate a drinking water equivalent level (DWEL) for perfluorooctanoic acid (PFOA) was applied to its extensive relevant information from human and laboratory animal studies. PFOA has been identified at 3.5 μg/L (mean) in tap water in proximity to a manufacturing facility; however, in most supplies, the levels were below 7.5 ng/L (usual limit of detection). PFOA has an average half-life in humans of 3.5 years. From animal studies, PFOA is considered a possible hepatotoxicant and developmental toxicant for humans. Based on two chronic studies, PFOA was judged to be a possible human carcinogen, whose mode-of-action was likely to be related to receptor activation but not genotoxicity. The Benchmark Dose-Uncertainty Factor approach was selected for dose–response for noncancer and cancer. Based on internal dose of PFOA, the DWEL protective against cancer is 7.7 μg PFOA/L tap water, and the noncancer DWELs range from 0.88 to 2.4 μg/L. These DWELs can be considered a reliable, albeit conservative, basis to set a Maximum Concentration Level Goal under the US Safe Drinking Water Act.