Undifferentiated brain tumors represent a diagnostic challenge, particularly in small biopsies, with regards to their primary versus metastatic origin. The latter may show overlapping morphologic features with primary high-grade brain tumors. In recent years several new antibodies have entered the realm of daily pathology practice. PAX8 (mammalian paired box genes 1 to 9 protein encoding gene) is among these new markers and is recognized as a differentiating marker of the primary site in epithelial tumors outside of the central nervous system. A review of the literature shows lack of site-specific studies with regards to the expression of PAX8 in the central nervous system and its neoplasms. Using this marker we investigated its immunohistochemical expression in normal brain tissue and glial tumors. The immunostain was performed on tissue microarrays of 71 cores from 24 cases. We also performed PAX8 immunostain on sections from cerebellum, pons, periventricular ependymal layer, choroid plexus, pituitary, and meninges of 3 autopsy cases. Our results indicate lack of PAX8 expression by benign brain tissue. Only 1 glioblastoma core (1/9 cores) showed focal nuclear reactivity with the antibody. Our results indicate that presence of PAX8 immunoreactivity in an undifferentiated brain tumor lacking gliofibrillary acidic protein expression should prompt consideration of a metastatic tumor.