Abstract: Mercury exposure has been associated with human deaths and several disease conditions including autoimmune diseases and cancers in experimental animals. At the cellular level mercury interacts with sulphydryl groups of proteins and enzymes, to damage DNA, and to modulate cell cycle progression and/or apoptosis. However, the underlying molecular mechanisms of mercury toxicity remain to be elucidated. The liver is one of the few organs capable of regeneration on injury implying that dormant genes in the liver are inducible and can be reactivated by xenobiotics. We therefore hypothesize that mercury-induced hepatotoxicity and related morbidities, is associated with the modulation of specific gene expressions that can lead to immune dysfunctions. To test this hypothesis, we used an Affymetrix oligonucleotide microarray with probe sets complementary to more than 20,000 genes to determine whether patterns of gene expression may differ between controls and mercury (1-3µg/mL) treated cells. Hierarchical cluster analysis identified several target genes that were affected. Fifty-three of these genes were up-regulated with greater than a two-fold change difference (p 0.002) in the lowest mercury concentration of 1µg/mL; showing a clear separation in their gene expression profile compared to the controls; twelve genes were moderately over-expressed with an increase of more than one fold (p 0.005); and 2023 were down-regulated although most of the decreases did not reach statistically significant levels (p<0.05) according to the Welch’s ANOVA/Welch’s t-test. Identified affected genes located on all human chromosomes with higher than normal effects on genes found on chromosomes 1-10, 12, 14-18, 20 that involved genes operating in the immune and cell cycle (cyclin-dependent kinases) pathways, apoptosis, cytokine expression, G-protein signal transduction, transcription factors, DNA repair as well as putative MAPK activating protein (PM20, PM21), ras homolog gene family, polymerase (DNA directed), regulatory subunit (50kDa), leptin receptor involved in hematopoietin/interferon-class (D200-domain) cytokine receptor activity and thymidine kinase 2, mitochondrial TK2 HGNC and related genes. Significant alterations in these specific genes provide new directions for deeper mechanistic investigations that would lead to a better understanding of the molecular basis of mercury-induced toxicity and human diseases that operate via disturbances in the immune responses leading to cancer. Keywords: Mercury, oligonucleotide microarray, gene expression profile, HepG2 cells, immune responses.