Signal regulatory protein (SIRP) α1 is a member of the SIRP family that undergoes tyrosine phosphorylation and binds SHP-2 tyrosine phosphatase in response to various mitogens. The expression levels of SIRPα1 were decreased in HCC tissues, compared with the matched normal tissues. Exogenous expression of wild type SIRPα1, but not of a mutant SIRPα1 lacking the tyrosine phosphorylation sites, in SIRPα1-negative Huh7 human HCC cells resulted in suppression of tumor cell growth both in vitro and in vivo. Treatment of Huh7 transfectants with EGF or HGF induced tyrosine phosphorylation of SIRPα1 and its association with SHP-2, which were accompanied by reduced ERK1 activation. Expression of SIRPα1 significantly suppressed activation of NF-κB and also sensitized Huh7 cells to TNFα or cisplatin-induced cell death. In addition, SIRPα1-transfected Huh7 cells displayed reduced cell migration and cell spreading in a fashion that was dependent on SIRPα1/SHP-2 complex formation. In conclusion, a negative regulatory effect of SIRPα1 on hepatocarcinogenesis is exerted, at least in part, through inhibition of ERK and NF-κB pathways. (HEPATOLOGY 2004;40:618–628.)