The transcription factor early growth response (Egr)−1 regulates the expression of genes required for execution of the wound healing response. Multiple cycles of injury, coupled to incomplete wound healing, lead to fibrosis. Therefore, we hypothesized that Egr-1 is required for the development of hepatic fibrosis. To test this hypothesis, we exposed wild-type and egr-1^−/− mice to acute or chronic carbon tetrachloride (CCl₄). Acute CCl₄ exposure established a profibrotic milieu in the liver, including activation of hepatic stellate cells as well as expression of type 1 collagen genes and tissue inhibitor of matrix metalloproteinase 1 in both wild-type and egr-1^−/− mice. This response was exacerbated in egr-1^−/− mice. After chronic CCl₄ exposure, hepatic fibrosis was established in both genotypes; however, the fibrotic response was profoundly worsened in Egr-1–deficient mice. Importantly, enhanced fibrosis in egr-1^−/− mice was accompanied by a robust activation of the oval cell response, suggesting more severe liver injury and/or reduced hepatocyte proliferation when compared with wild-type mice. Hepatic expression of genes indicative of oval cell activation, as well as the number of cells expressing A6, a mouse oval cell marker, was greater in egr-1^−/− mice. Taken together, these data reveal novel roles for Egr-1 as a negative regulator of both CCl₄-induced hepatic fibrosis and the oval cell response.