A selective cyclooxygenase-2 (COX-2) inhibitor has been previously shown to suppress the hyper-induced pro-inflammatory responses in H5N1 infected primary human cells. Here, we demonstrate that COX-2 inhibitors suppress H5N1 virus replication in human macrophages suggesting that H5N1 virus replication (more so than seasonal H1N1 virus) is dependent on activation of COX-2 dependent signaling pathways in host cells. COX-2 and its downstream signaling pathways deserve detailed investigation as a novel therapeutic target for treatment of H5N1 disease.