Soluble forms of major histocompatibility complex (MHC) class I-related chain A and B (MICA/B) are increased in the sera of patients with malignancy and impair the antitumor immune response by downregulating expression of their cognate immunoreceptor natural killer group 2, member D (NKG2D). Recently, soluble MICA/B were reported to appear even in some premalignant diseases, raising questions about the impact of soluble MICA/B produced from tumors on the expression of NKG2D. The present study examined soluble MICA/B in chronic liver disease and hepatocellular carcinoma (HCC) and their involvement in the immune-cell expression of NKG2D during transcatheter arterial embolization for HCC. The levels of soluble MICA/B were significantly higher in chronic liver disease and HCC patients than in healthy volunteers. The progression of liver disease and that of the tumor were independent determinants for soluble MICA/B levels. Immunohistochemistry revealed that MICA/B were expressed not only in HCC tissue but also on hepatocytes in cirrhotic livers. The transcatheter arterial embolization therapy significantly decreased serum levels of soluble MICA, but not soluble MICB, and increased the NKG2D expression on natural killer cells and CD8-positive T cells; there was an inverse correlation between changes in soluble MICA levels and in NKG2D expression. In conclusion, although soluble MICA/B are produced from both HCC and premalignant cirrhotic livers, therapeutic intervention for HCC can reduce the levels of soluble MICA and thereby upregulate the expression of NKG2D. Cancer therapy may have a beneficial effect on NKG2D-mediated antitumor immunity.