['Interferon (IFN)-α is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-α treatment in lung metastasis are not yet clear.', 'The effect of IFN-α treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis. Pretreatment with IFN-α before implantation of tumor was done to explore the effect of IFN-α on lung tissues. Cytokines and macrophages were measured by immunohistochemistry and/or PCR assay, using human origin or mouse origin primers to differentiate the sources. Circulating tumor cells (CTCs) were also assayed by flow cytometry.', 'IFN-α treatment did not decrease the number of CTCs (0.075% ± 0.020% versus 0.063%±0.018%, P\u200a=\u200a0.574, IFN-α-treated versus control groups), but did decrease the number and size of lung metastasis (number: 1.75 ± 1.0 versus 28.0 ± 6.3, P\u200a=\u200a0.008; size [pixels]: 116.8 ± 72.2 versus 5226.4 ± 1355.7, P\u200a=\u200a0.020), and inhibited macrophage infiltration (0.20% ± 0.04% versus 1.36% ± 0.21%, P\u200a=\u200a0.0058) and alteration of matrix metalloproteinase (MMP)-9 expression (mean integrated optical density (IOD): 5.1 ± 1.7 versus 21.9 ± 0.4, P<0.000) in the lung, which was independent of the primary tumor.'] Does direct transformation of lung microenvironment by interferon-α treatment counteract growth of lung metastasis of hepatocellular carcinoma?