Administration of 2‐acetylaminofluorene (2‐AAF) given before partial hepatectomy (PHx) results in suppression of hepatocyte proliferation and stimulation of oval cell proliferation. Our objective in this study was to examine the oval cell response and associated α‐fetoprotein (AFP) gene expression by combining 2‐AAF with selective damage of centrilobular regions (carbon tetrachloride [CCl₄ ]) or periportal regions (allyl alcohol [AA]). Centrilobular damage results in a more enhanced oval cell response and AFP gene expression than periportal damage. Conversely, more intense proliferation of intraportal bile duct epithelia was seen with 2‐AAF/AA than with 2‐AAF/CCl₄ . The oval cell response and AFP gene expression was ranked as 2‐AAF/CCl₄ ≥ 2‐AAF/PHx > 2‐AAF/AA. AFP mRNA expression was also examined in an acute AA and CCl₄ injury. We found very little AFP gene expression compared with the 2‐AAF/hepatic injury models. To see a true oval cell response, the hepatocytes must be inhibited from proliferating. In addition, the results presented with the 2‐AA/AA model suggest that the periportal matrix may be as important as the cells that populate the area.