The in vivo‐in vitro DNA repair and DNA replication assay in mouse hepatocytes has promise as a short‐term test for detecting potential mouse liver carcinogens. In addition, this assay may provide information on the mode of action of known hepatic carcinogens. The induction of DNA repair is clearly a response to hepatic DNA damage. However, it is unclear whether induction of replicative DNA synthesis (S phase) represents regenerative hyperplasia in response to hepatotoxicity or is a result of direct mitogenic stimulation of the hepatocytes by the test compound. The objective of the present study was to examine the relationship between hepatotoxicity, which was assessed by measuring serum concentrations of glutamic‐oxalacetic transaminase (SCOT), glutamic‐pyruvic transaminase (SCPT), alkaline phosphatase (AP), and gammaglutamyl transferase (CGT), and induction of S phase following either single or multiple doses of the model mouse hepatocarcinogen carbon tetrachloride (CCI4).