The Raf-MEK-ERK signaling pathway is important during oncogenesis. An activating mutation of BRAF constitutively activates the Raf-MEK-ERK signaling cascade, and has been identified in ~70% of malignant melanomas (MMs). Cluster of differentiation 147 (CD147)/basigin is an integral plasma membrane protein belonging to the immunoglobulin superfamily. The protein is highly expressed on MM cells, and promotes cellular proliferation and tumor growth. The present study investigated the correlation between CD147 expression and Raf-MEK-ERK signaling in MM using the A375 human MM cell line, which harbors the activating mutation of BRAF. The phosphorylation of epidermal growth factor receptor (EGFR) was upregulated, and mitogen-activated protein kinase kinase (MEK) and cell division cycle 25C phosphorylation was downregulated by CD147 silencing in the A375 cells. Cell growth was inhibited by the EGFR inhibitor erlotinib and by CD147 silencing, and additive growth inhibition was observed when these techniques were combined. The results of the present study indicate that the combination of EGFR and CD147 inhibition may be useful in BRAF-mutated MM.