Although accumulating evidence had revealed that NFAT1 has oncogenic characteristics, the role of this molecule in melanoma cells remains unclear. Previous studies proved that CD147 plays a crucial function in melanoma cell metastasis and invasion through matrix metalloproteinase 9 (MMP-9) expression; however, the details of how CD147 regulates MMP-9 expression remain elusive. In this study, we demonstrated that CD147 and NFAT1 are overexpressed in the tissues of patients with primary and metastatic melanoma, which has shown a positive correlation. Further, we observed that CD147 regulates NFAT1 activation through the [Ca ]i-calcineurin pathway. Knock down of NFAT1 significantly suppresses melanoma metastasis, and we demonstrated that CD147 affects melanoma metastasis in an NFAT1-dependent manner. Moreover, we verified that NFAT1 directly binds to MMP-9 promoter. Inhibition of CD147 expression significantly abrogates MMP-9 promoter luciferase gene reporter activity as well as NFAT1 association with MMP-9 promoter. Taken together, this study demonstrated that CD147 affects MMP-9 expression through regulating NFAT1 activity and provided a novel mechanism by which NFAT1 contributes to melanoma metastasis through the regulation of MMP-9.This article is protected by copyright. All rights reserved.