Background: Hemangioblastomas account for up to 2.5% of all intracranial tumors. They may occur sporadically or as a part of the multisystem genetic syndrome of Von Hippel-Lindau syndrome (VHL). Patients with VHL are also at an increased risk of developing clear cell renal cell carcinoma (ccRCC). Distinguishing hemangioblastomas from metastatic ccRCC to the central nervous system (CNS) can be challenging at times when based solely on hematoxylin and eosin-stained sections. We propose an immunohistochemistry (IHC) panel of combination of PAX2, PAX8, and inhibin A as a helpful approach in distinguishing the 2 lesions. DESIGN: Archival tissues from 20 hemangioblastomas and 16 ccRCCs metastatic to the CNS were retrieved from our surgical pathology files (2001 to 2010). IHC for PAX2, PAX8, and inhibin A was performed on routine or tissue microarray sections using standard IHC protocol. The intensity of nuclear staining was evaluated for each marker and was assigned an incremental 0, 1+, 2+, and 3+ score. The extent of staining was categorized as focal (<25%), multifocal (25% to 75%), or diffuse (>75%). Result: (1) Hemangioblastoma: The Von Hippel-Lindau syndrome was diagnosed in 4 of 16 (25%) patients, 2 of whom developed multiple hemangioblastomas. All 20 (100%) hemangioblastomas were positive for inhibin A (cytoplasmic). The staining intensity was moderate or strong (2+ or 3+) in 19 cases (95%), all of which were multifocal or diffuse in extent. Nuclear PAX2 staining was present in 1 of 19 evaluable lesions (5%), whereas PAX8 staining was not present in any of the 20 examined lesions. (2) Metastatic ccRCC to the CNS: Fourteen of 16 (88%) examined ccRCCs were positive for PAX2, whereas 15 of 16 (94%) lesions showed PAX8 staining. None of 16 (0%) examined ccRCCs were positive for inhibin A. Conclusions: We propose the use of the combination of PAX2, PAX8, and inhibin A as a helpful ancillary IHC panel to resolve the differential diagnosis of hemangioblastoma versus metastatic ccRCC. The immunoprofile of PAX2(+) or PAX8(+) and inhibin A(-) supports the diagnosis of metastatic ccRCC with a sensitivity of 94%, specificity of 100%, and positive predictive value of 100%. The PAX2(-), PAX8(-), and inhibin A(+) profile supports the diagnosis of hemangioblastoma with a sensitivity of 95%, specificity of 100%, and positive predictive value of 100%. Copyright © 2011 by Lippincott Williams & Wilkins.