Progressively enlarging encephalopathic changes are now well-documented effects of gamma knife radiosurgery (GKRS) occurring ~3-30 months after treatment of both benign and malignant brain lesions. These changes can be variably associated with inflammatory demyelination and necrosis and/or recurrent tumor. While radiographic differentiation between encephalopathic changes and recurrent tumor is of high clinical relevance, confident interpretation of post-radiosurgery imaging changes can be challenging or even impossible in some cases. Gadolinium-enhanced MRI of these lesions reveals variable amounts of enhancing and non-enhancing components within these lesions that have not been clearly correlated with structural-pathologic change. The goal of this study is to characterize the histopathological changes associated with enhancing versus non-enhancing regions of GKRS-treated lesions. MRI images of patients with progressive, etiologically ambiguous brain lesions following GKRS were reviewed prior to explorative neurosurgery. Chosen for this study were lesions in which distinct areas of enhancement and non-enhancement of at least 5 mm in size could be identified (n = 16). Distinctly enhancing and non-enhancing areas were separately biopsied and histologically evaluated. Only cases with uniform histological results are presented in this study. Enhancing and non-enhancing areas in post GKRS lesions represent separate pathological changes. Radiographically enhancing areas correlate either with recurrent tumor growth or inflammatory demyelinating changes. Lack of radiographic enhancement correlates with coagulative necrosis if the sample is taken from the center of the lesion, or with reactive astrocytosis if the sample is taken from the periphery. Separate biopsy of enhancing and non-enhancing regions of post-GKRS encephalopathy was able to confirm that the pathologies in these areas are distinct. These findings allow for better-informed correlation of histological and radiological changes and a better understanding of post-treatment tissue pathology.