The aim of this study was to investigate the differences of the microRNA (miRNA) expression profiles in mouse lungs infected with wild type low pathogenic H5N2 avian influenza A (w81) or mouse-adapted virulent H5N2 avian influenza A (ma81) virus. Different sensitivities of influenza A virus strains to the hosts cause variations in miRNA expression. Therefore, some of miRNAs can be used as potential prognostic targets during the avian influenza A virus infections in mammalian hosts. Five-week-old C57BL/6 female mice were inoculated with 30 ul of 10⁴ TCID₅₀ of w81 or ma81. Lung tissues from 3 mice per group were harvested at 1 and 3 dpi. A small RNA library was constructed from the total RNAs of lung samples and sequenced using the Solexa platform. Sequence reads were normalized to determine the number of transcripts per million, and fold changes of miRNAs were evaluated. P-value was calculated using following formula as previously described. p(x|y) = (N2/N1) (x+y)!/x!y!(1 + N2/N1)(x +y + 1) where x, y, N1, and N2 represent number of miRNAs surveyed, number of homologous miRNAs in controls, total number of clean reads in controls, and total number of clean reads in treatments, respectively. Gene ontology analysis was conducted by miRanda and DAVID. The w81 virus induced a higher number of differentially expressed miRNAs compared with the ma81 virus. It is interesting to see that only 9 miRNAs (miR-100-5p, miR-130a-5p, miR-146b-3p, miR-147-3p, miR-151-5p, miR-155-3p, miR-223-3p, miR-301a-3p, and miR-495-3p) were significantly upregulated in both lungs infected either with the w81 or ma81 strain at both time point (P < 0.05). Especially, expression levels of 4 miRNAs were higher in the lungs of mice infected with the ma81 virus than those infected with the w81 virus (P < 0.05). These 4 miRNAs have been implicated in immune responses (miR-223-3p and miR-147-3p), viral infection (miR-155-3p), and cell migration (miR-151-5p). Our results suggest that the mammalian adaptation of avian influenza A virus results in a different miRNA expression pattern in lungs of virus-infected mice compared with its parental strain. Thus these might be used as potential prognostic targets during the avian influenza A virus infections in mammalian hosts.