The parasite Entamoeba histolytica colonizes the large bowel where it may persist as an asymptomatic luminal gut infection, which changes to virulence. Parasite invasion of the intestine leads to dysentery and spreads to the liver, where amoebae form abscesses. We took advantage of changes in virulence that occurs after long-term in vitro culture of E. histolytica strains. Using microarrays, we concluded that virulence correlates with upregulation of key genes involved in stress response, including molecular chaperones, ssp1 and peroxiredoxin; as well as the induction of unknown genes encoding lysine-rich proteins. Seven of these were retained with respect to their lysine content higher than 25%. Among them, we found KERP1, formerly identified as associated to parasite surface and involved in the parasite adherence to host cells. Experimentally induced liver abscesses, using molecular beacons and protein analysis, allowed us to draw a parallel between the intricate upregulation of kerp1 gene expression during abscess development and the increased abundance of KERP1 in virulent trophozoites. Following its characterization as a marker for the progression of infection, KERP1 was also seen to be a virulence marker as trophozoites affected in kerp1 expression by an antisense strategy were unable to form liver abscesses.