The authors present the case of a patient that demonstrates the long-standing use of megestrol acetate, a progesterone agonist, and its association with multiple intracranial meningioma presentation. Discontinuation of megestrol acetate led to shrinkage of multiple tumors and to the complete resolution of one tumor. Histological examination demonstrated that the largest tumor had high (by > 25% of tumor cell nuclei) progesterone-positive expression, including progesterone receptor (PR) isoform B, compared with low expression of PR isoform A; there was no evidence of estrogen receptor expression and only unaccentuated collagen expression. This is the first clinical report illustrating a causal relationship between exogenous hormones and modulation of meningioma biology in situ.