BACKGROUND Aberrant progesterone signaling has been demonstrated in mechanistic studies to be a shared common pathway in fibroids and endometriosis. Progesterone receptor modulation with the selective progesterone receptor modulator (SPRM) ulipristal may decrease pain associated with endometriosis. METHODS A 25-year-old nulligravidae with endometriosis-related pelvic pain refractory to medical and surgical intervention was administered 15mg ulipristal every other day for 3 months. Daily pain scores and bleeding diary were recorded and serum chemistries and hormone levels were checked prior to, during, and after treatment. Pre-treatment and surveillance endometrial biopsy specimens were examined for histology and stained for estrogen and progesterone receptor status. During therapy, pain scores decreased to a median of 0 (P<0.05) and the patient became amenorrheic. Surveillance endometrial biopsy demonstrated SPRM-associated endometrial changes that appeared strikingly similar to simple hyperplasia and resolved with ulipristal discontinuation. Immunohistochemical evaluation demonstrated the presence of estrogen and progesterone receptors before and during ulipristal treatment. CONCLUSIONS Progesterone receptor modulation with ulipristal substantially improved pain symptoms in a patient with treatment-refractory endometriosis. SPRM-associated changes in the endometrium closely mimicked hyperplasia, developed after less than three months of treatment, and resolved after discontinuation of ulipristal and induction of withdrawal bleed.