Viral hepatitis A and B are known to cause acute liver failure. While nearly 20% of acute liver failure cases are of indeterminate etiology, screening for other viruses has not been uniformly performed. We looked for evidence for parvovirus B19 and hepatitis E virus in sera from U.S. acute liver failure patients. For B19, 78 patients’ sera, including 34 with indeterminate etiology, were evaluated by DNA dot-blot hybridization, reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay for immunoglobin G and M antibodies; none showed evidence for infection. In like manner, 126 patients’ sera were analyzed for hepatitis E virus RNA by reverse transcription polymerase chain reaction and for hepatitis E virus immunoglobin G and M antibodies by enzyme-linked immunosorbent assay; no acute hepatitis E virus cases were identified. If a unique acute liver failure virus exists, it is neither of these candidate agents.