Hepatitis C virus (HCV) core protein plays a significant role in the alteration of cellular gene expression. We expressed HCV core protein using a tetracycline-inducible expression system in HeLa cell lines. Profiles of gene expression in cells expressing the HCV core protein were compared with those in control cells by use of microarray analysis. Cells expressing the HCV core protein showed 86 down-regulated and 41 up-regulated genes, compared with control cells. One gene affected was cyclooxygenase 2 (COX-2). Levels of both COX-2 RNA and the Cox-2 protein were significantly inhibited after the expression of HCV core protein in HeLa cells. Similar results were obtained in hepatoma cells and in a functional assay that measured the production of the Cox-2 protein in response to a mitogenic stimulus. The inhibition of the Cox-2 protein could serve as a means of muting the cellular inflammatory response during HCV infection. Correlation of these findings with analysis of clinical specimens from chronically infected patients should lend further significance to the down-regulation of the inflammatory response via Cox-2.