Cancer cells require glycolysis for energy; this results in excessive lactate production and secretion. Lactate, the end product of glycolysis, reduces the extracellular pH and contributes to the proliferation, invasiveness, metastasis, and angiogenesis of tumor cells. Our previous results revealed that the over-expressed CD147/basigin plays a critical role in malignant melanoma (MM) invasiveness, metastasis and angiogenesis; CD147 has also been implicated in a specific and strong interaction with monocarboxylate transporters (MCT) 1 and 4 that mediate the transport of lactate. In the present study, we investigated whether CD147/basigin is involved, via its association with MCT1 and 4 to transport lactate, in glycolysis and then contributes to the progression of A375 melanoma cells. A375 cells expressed remarkably higher CD147, MCT1 and 4 and showed increased glycolysis rate compared with normal human melanocytes (NHMC). CD147/basigin co-localized with MCT1 and 4 in the A375 cell membrane. Furthermore, silencing of CD147/basigin in A375 cells by a siRNA clearly abrogated the expression of MCT1 and 4 and their co-localization with CD147/basigin and dramatically decreased the glycolysis rate, extracellular pH, and the production of ATP. Thus, cell proliferation, invasiveness, and VEGF production were significantly decreased by siRNA. These results strongly suggest that highly-expressed CD147 interacts with MCT1 and 4 to promote tumor cell glycolysis, resulting in the progression of MM.