We previously reported that microarray expression profiling identified several candidate genes in association with interferon-alpha (IFN-alpha) response in renal cell carcinoma (RCC) cell lines (Cancer Sci 2007; 98: 529). Among them, we focused on microphthalmia-associated transcription factor (MITF), because its expression profile correlated well with IFN-alpha-response status. In addition, we investigated the clinical significance of the expression level of MITF using surgical specimens. RNA was extracted from 14 RCC cell lines and 65 RCC samples and was used in this study. Transfection of MITF cDNA into IFN-alpha-resistant RCC cell lines resulted in elevation of MITF expression and acquisition of IFN-alpha-sensitivity by quantitative PCR and WST-8 assay, respectively. Statistical analysis revealed that low MITF mRNA expression in RCC samples was significantly correlated with the presence of metastasis and poor survival of the patient. However, the correlation between MITF expression and IFN-alpha response was not obvious in the clinical cases. MITF gene transfection elevated IFN-alpha-sensitivity in RCC cell lines, suggesting that this gene is a target molecule for modulation of the IFN-alpha response. Quantification of MITF mRNA expression might be clinically useful to predict metastasis and survival of patients with RCC.