Virulent avian influenza A viruses produce lethal disease in chickens. Since cell death can be caused by either necrosis or apoptosis, we investigated the types of cell death that occur in natural hosts, chickens, infected with virulent avian viruses. Using biochemical methods, we demonstrate that virulent avian influenza viruses induce apoptosis of vascular endothelial cells in liver, kidney, and brain. Viral antigens were also detected in these organs, suggesting that viral replication induces apoptosis in infected chickens. These results indicate that apoptosis does occur in virulent avian influenza virus infection in a natural host, and may contribute to the lethality of the virus.