Background/Aims: The liver has the unique capacity to restore its mass by hepatocyte proliferation after injury or transplantation. The present study investigated whether the regenerating liver responds to immune stimuli in the same way as the quiescent one. Methods: We performed partial hepatectomy (PHx) in mice, then stimulated the mice with concanavalin A (ConA) to study their immune responses. Plasma Alanine aminotransferase (ALT) and cytokine levels as well as liver inflammatory infiltration were measured to evaluate liver damage. Transcriptional factors were further detected to study the underlining mechanisms. Results: Our results showed that PHx mice were resistant to ConA-induced liver inflammation and injury, as evidenced by both morphological and biochemical observations. Then we went further to study the mechanisms. We found marked signal transducer and activator of transcription 3 (STAT3) activation 48 hours after PHx. When STAT3 activation was blocked with its inhibitor JSI-124, PHx mice also developed severe liver inflammation after ConA stimulation. Conclusion: The regenerating liver is resistant to ConA induced immune assaulting, and STAT3 is the major player in the protection process. Copyright © 2009 S. Karger AG, Basel.