Keratoacanthoma is a unique skin tumor which shows similar histopathologic features to SCC, but regresses voluntarily after rapid growth. Recently, there have been cases in which secondary cancer has been induced by a new anti-cancer drug. Vemurafenib is used for treatment of metastatic and unresectable melanomas with V600E mutations in the BRAF gene. BRAF is a component of the mitogen-activated protein kinase (MAPK) pathway, leading to RAS-RAF-MEK-ERK which is involved in cell proliferation, survival, and differentiation. Mutations in the BRAF gene cause a permanent activation of B-RAF and by extension, of the MAPK pathway, which results in uncontrolled growth and proliferation of cells. Vemurafenib, small-molecule inhibitor of BRAF(V600E) kinase, cause an inhibition of an over-activated MAPK signaling pathway downstream in BRAF kinase-expressing tumor cells. Proliferation of keratinocytes is common when using Vemurafenib, ranging from benign verrucous lesions to malignant. It usually occurs between the 7th and 8th weeks of treatment. In our two cases, a 58-year-old man and a 66-year-old woman, who had metastatic melanoma, were referred because of keratotic papules and nodules on face and neck. Both patients were treated with Vemurafenib for two and three months. We performed skin biopsy and the skin lesions of the both patients were diagnosed as keratoacanthoma. We report two cases of B-RAF enzyme inhibitor associated keratoacanthoma.