The sulfur-containing compound, S-allyl-L-cysteine (SAC), is found in aged garlic extract. The pharmacological study of SAC has included many reports of its antioxidant activities, however, little information has been accumulated regarding SAC-induced proliferation in various cell types. Previously, we reported that SAC is a mitogenic effector of normal remnant liver in two-thirds partially hepatectomized rats. The purpose of this study was to investigate the mechanism of cell proliferation induced by SAC using specific inhibitors of signal transducers in primary cultures of adult rat hepatocytes. We showed that SAC induced time- and dose-dependent hepatocyte proliferation in primary cultures of adult rat hepatocytes. Hepatocyte mitogenesis induced by SAC was inhibited by a selective IGF-1 receptor tyrosine kinase inhibitor AG538, a selective PI3 kinase inhibitor LY294002, a selective MEK inhibitor PD98059, a selective mTOR inhibitor rapamycin, and granule secretion inhibitor somatostatin. Furthermore, a monoclonal antibody against IGF-1 dose-dependently inhibited the SAC-induced cell proliferation. Our observations showed that the mitogenic effect of SAC was dependent on autocrine secretion of IGF-1 and secreted IGF-1 by SAC stimulates the IGF-1 RTK / PI3K / MEK / ERK / mTOR pathway to promote hepatocyte proliferation.