Liver regeneration is a complex, systemic process regulated by humoral and cellular mechanisms. Inflammatory response to the extensive tissue damage, as in partial hepatectomy, plays important role during regeneration. Hence, it is assumed that the spleen might play a role in systemic inflammatory response involved in liver regeneration. On the other hand, liver damage and consequential regeneration are often associated with oxidative stress and lipid peroxidation. One of the end products of lipid peroxidation, 4-hydroxynonenal (HNE), is nowadays considered not only as a "second toxic messenger of free radicals" but also as a growth-regulating factor. We therefore studied in vitro interactions of the HNE-treated murine liver cells and autologous spleen cells. The spleen cells supported recovery of liver cells from the HNE cytotoxicity although spleen cells themselves exerted cytotoxic effects against the proliferating liver cells that were not treated with HNE. Our results imply that the cytokines secreted by activated immunocompetent cells may be responsible for the observed recovery of the HNE-damage liver cells, suggesting that HNE might be an important factor regulating cellular and cytokine mediated mechanisms of liver regeneration control.