Acute hemorrhagic disease caused by elephant endotheliotropic herpesvirus (EEHV) infection is well recognized as a major threat to young Asian elephants (Elephas maximus) but has been less frequently documented in African elephants (Loxodonta africana). This report describes five sequential cases of EEHV3A infection in African elephants in managed care at one institution. All elephants developed disease within a 4-mo period. The first two cases were 6.5- and 7.5-yr-old females that presented with depressed mentation, anorexia, hematuria, and diarrhea. Both elephants died within 48–72 hr of the onset of illness despite treatment. Postmortem findings included widespread edema, ascites, and extensive petechiae and ecchymoses on the heart, liver, and spleen and within the gastrointestinal and urogenital tracts. Histologic examination identified disseminated vascular necrosis with edema, hemorrhage, and rare endothelial cell intranuclear inclusions typical of herpesvirus in multiple organs. The third and fourth cases were a 13-yr-old male and a 12-yr-old female that presented with minimal to no clinical signs, but with marked changes in hematologic parameters and high viremia detected by quantitative polymerase chain reaction (qPCR). Both elephants survived the infection with early and aggressive treatment. The fifth case was a 37-yr-old female that presented with lethargy and a decreased appetite. Low viremia was detected by qPCR, and mild to moderate hematologic changes were noted. Early treatment resulted in a successful outcome. This case series documents the first known reports of clinical disease and fatality associated with EEHV3A in African elephants.