Sorafenib is a multi-kinase inhibitor for the treatment of advanced hepatocellular carcinomas. It inhibits tumor cell proliferation and tumor angiogenesis by targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptor, c-Kit and Raf-1. Although sorafenib is reported as effective treatment for them, it has also been known to cause diverse cutaneous adverse reactions including hand-foot reaction, facial and scalp eruptions, alopecia and pruritus. However, the mechanism of these adverse effects has not been well-investigated. Mast cells (MC)s are reported to be associated with drug eruptions and pruritus. Here we focused on skin type MC biology by using human skin organ culture system treated with sorafenib and skin samples from patients with drug eruption by sorafenib. As a result, sorafenib significantly activated MC degranulation and increased both c-Kit and tryptase positive MC number in situ. However, sorafenib did not affect MC proliferation and apoptosis. This suggests that sorafenib stimulated MC maturation from resident precursor cells. Furthermore, sorafenib significantly increased the expression of Akt but not Erk within c-Kit positive MCs. Importantly, a PI3K inhibitor, wortmannin abrogated the increased number of MCs by sorafenib. This suggests that the compensatory upregulation of PI3K-signaling was induced by the inhibition of MAP kinase signaling by sorafenib. Sorafenib also significantly upregulated the expression of stem cell factor (SCF), a well-known MC growth factor within the epidermis of organ cultured skin samples. In addition, co-administration of SCF neutralizing antibody diminished the increase in MC number by sorafenib. When we investigated MCs biology within the skin samples from the patients with sorafenib induced drug eruptions, both the number of degranulated and total MCs was significantly increased. Our results indicate that sorafenib is a new activator for human skin type MCs degranulation and maturation, and MCs could be a new target for treating adverse effects by sorafenib.