Abstract Infections with highly pathogenic H5N1 avian (HPAI) and 1918 pandemic H1N1 influenza viruses cause uncontrolled local and systemic inflammation. The mechanism for this response is poorly understood, despite its importance as a determinant of virulence. Therefore we profiled cellular microRNAs of lung tissue from cynomolgus macaques ( Macaca fascicularis) infected with a HPAI and a less pathogenic 1918 H1N1 reassortant virus to understand microRNA contribution to host response. We identified 23 microRNAs associated with the extreme virulence of HPAI, with expression patterns inversely correlated with that of predicted gene targets. Pathway analyses confirmed that these targets were associated with aberrant and uncontrolled inflammatory responses and increased cell death. Importantly, similar microRNAs were associated with lethal 1918 pandemic virus infections in mice. This study suggests that virulence of highly pathogenic influenza viruses may be mediated in part by cellular microRNA through dysregulation of genes critical to the inflammatory process.