Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly and that promote immunosuppression. According to our previous in vivo report, we evaluate the details of the apoptotic mechanism in liver, we have investigated how copper regulates apoptotic pathways in liver. We have analyzed different protein expression by Western blotting and immunohistochemistry expression. We have also have measured mitochondrial trans-membrane potential, Annexin V assay, ROS, and CD4+ and CD8+ population in hepatocyte cells by flow cytometry. Copper-treated mice evidenced immunotoxicity as indicated by dose-related, distinct histomorphological changes in liver. Flow cytometric analyses revealed a dose-related increase in the percentages of hepatocyte cells in the Sub-G0/G1 state, further confirmed by Annexin V binding assay. In addition, the copper treatments altered the expression of apoptotic markers, further ROS generation and mitochondrial trans-membrane potential changes promote intrinsic pathway of apoptosis that was p53 independent. Apart from the role of inflammation, our findings also have identified the role of other partially responsible apoptotic molecules p73 that differentially changed due to copper treatment. Our study demonstrates how apoptotic pathways regulate copper-induced immunosuppression in liver. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 411–421, 2015.