We previously reported that S-allyl-L-cysteine (SAC)-induced cell proliferation was involved in intracellular IGF-I secretion via Janus kinase 2 (JAK2) / phospholipase C (PLC) pathway in primary cultures of adult rat hepatocytes. In this study, we investigated the involvement of IGF-I receptor tyrosine kinase (RTK) in the SAC-induced hepatocyte proliferation by using Western blot analysis. IGF-I RTK (p95 kDa) phosphorylation in cultured hepatocytes peaked 20 min after SAC stimulation. SAC-induced IGF-I RTK phosphorylation was suppressed not only by the IGF-I RTK inhibitor AG538 but also by the JAK2 inhibitor TG101209 and the PLC inhibitor U-73122. Furthermore, the SAC-induced cell proliferation was significantly suppressed by PI3 kinase inhibitor LY294002, MEK inhibitor PD98059, and mTOR inhibitor rapamycin. These results suggested that the SAC-induced IGF-I RTK phosphorylation is mediated by JAK2/PLC phosphorylation and subsequently released IGF-I phosphorylates IGF-I RTK. Then hepatocyte proliferation may be induced via IGF-I RTK / PI3 kinase / MEK / mTOR pathway.