The present case reports the concurrence of endometriosis of the vaginal cuff with endometrial stromal sarcoma in association with high-dose estrogen. This case raises the question of whether chronic high-dose estrogen might be associated with malignant transformation of endometrial stroma. Although there is no definitive evidence of a causal relation between estrogen and endometrial stromal sarcoma, the possibility should be explored further. Therapy of this neoplasm is discussed and salient clinical and pathologic features are reviewed.