Highly pathogenic avian influenza virus infection is characterized by a marked inflammatory response, but the impact of infection on dendritic cells (DCs) is unknown. We show that influenza A virus subtype H5N1 infection rapidly and profoundly impacts DCs in cynomolgus macaques, increasing the number of blood myeloid and plasmacytoid DCs by 16- and 60-fold, respectively. Infection was associated with recruitment, activation, and apoptosis of DCs in lung-draining lymph nodes; granulocyte and macrophage infiltration in lungs was also detected, together with expression of CXCL10. This degree of DC mobilization is unprecedented in viral infection and suggests a potential role for DCs in the pathogenesis of highly pathogenic avian influenza virus.