BACKGROUND: Endometrial stromal sarcoma typically is of low grade and hormone-sensitive. Although these characteristics result in an indolent behavior, little data are available on the evolution over time. CASE: We report on two cases where microscopic and immunohistochemic assessment of the tumor on several occasions during 8 and 25 years of follow up enabled us to document a transition of a low-grade into a high-grade malignancy. These were mainly characterized by increased cellular atypia, absence of spiral arterioles and an increased mitotic index and proliferation index (MIB1). Since this transition was related to clinical loss of hormone sensitivity, the therapeutic approach consisting of hormonal treatment in combination with repetitive surgery was switched to chemotherapy only. CONCLUSION: These long-term follow up data provide insight in endometrial stromal sarcoma tumor biology and highlight the importance of sampling recurrent tumors to estimate biologic behavior in order to tailor subsequent treatment.