Rift Valley fever (RVF) is an important viral zoonotic disease in Africa with periodic outbreaks associated with severe disease, death, and economic hardship. During the 2006-2007 outbreaks in Eastern Africa, postmortem and necropsy tissue samples from 14 animals and 20 humans clinically suspected of RVF were studied with histopathologic evaluation and immunohistochemical (IHC) assays. Six animal and 11 human samples had IHC evidence of Rift Valley fever virus (RVFV) antigens. We found that extensive hepatocellular necrosis without prominent inflammatory cell infiltrates is the most distinctive histopathologic change in liver tissues infected with RVFV. Pathologic studies on postmortem tissue samples can help establish the diagnosis of RVF, differentiating from endemic diseases with clinical manifestations similar to RVF, such as malaria, leptospirosis, or yellow fever.