Hepatitis B virus (HBV) replicates in most tumor tissues of patients with HBV-associated hepatocellular carcinoma (HCC). In the present study, we have shown that the expression of HBV in the HCC cell lines, HepG2 and Huh7, down-regulated the expression of MHC class I-related molecule A (MICA), a ligand of the NKG2D receptor. Inhibition of HBV expression by small interference RNAs (siRNAs) in HepG2.2.15, a cell line that constitutively expresses HBV, induced up-regulation of MICA. The up-regulation of MICA increased the lysis of HepG2.2.15 cells by NK cells. Our results suggest that HBV compromises the innate immune system in HCC patients and that inhibition of HBV replication by siRNAs may enhance the antitumor immune response.