Haptoglobin (Hp), an acute-phase response protein, is typically increased in the serum of adults after acute tissue injury. It is an antioxidant and may function as an injury-induced neuroprotective protein. However, the source of increased Hp is not clear. To investigate its source, we compared its time course expression profile in serum from rats with or without traumatic brain injury (TBI). Elevated Hp levels revealed by proteomic analysis were confirmed by Western blot, semiquantitative PCR, and real-time PCR. We found that Hp protein and mRNA levels were increased after TBI in both serum and liver, especially in liver. Both in vivo and in vitro data showed that Hp expression was increased in rat and human (HL7702) liver cells upon treatment with TBI serum. Addition of anti-interleukin-6 (IL-6) antibody downregulated the expression of Hp in liver cells induced by serum derived from rats and in liver of rats after TBI. These findings suggest that the increased Hp in serum came from the liver in response to TBI and that IL-6 is an important mediator of this induction. © 2012 Wiley Periodicals, Inc.