Tumors with identical phenotype can have markedly different biologic behavior. The differentiation between hemangioblastoma, a benign vascular brain tumor, and renal cell carcinoma (RCC), a malignant tumor that can metastasize to the brain, is a well-known pathological quandary. We report a 59-year-old female with von Hippel-Lindau disease and known RCC. She presented with a cystic cerebellar tumor that had typical MRI appearance of a hemangioblastoma. Progressive symptoms led to surgical intervention. The histology included features consistent with either hemangioblastoma with epitheloid phenotype or atypical RCC metastasis mimicking hemangioblastoma. The discrepancy between the benign clinical course and the histologic phenotype could not be clearly resolved using conventional clinical techniques. We used proteomic profiling to clarify this diagnostic dilemma. We compared the proteomic expression pattern of the unknown lesion with the patterns of three typical hemangioblastomas and three typical RCCs by using selective tissue microdissection combined with two-dimensional proteomic profiling and protein sequencing. The results clearly indicated a protein profile consistent with RCC. Proteomics may complement pathological evaluation and characterization of tumors in the future. Furthermore, these results show that metastasis of malignant RCC is not necessarily equivalent to aggressive growth patterns.