Endometriosis has been considered an estrogen-dependent chronic inflammatory disease affecting women of reproductive age. Recent evidence suggests a shift in this paradigm, considering the possible occurrence of de novo endometriosis diagnosis in postmenopausal women. The present study aims to help understanding the pathophysiology and clinical management of such enigmatic entity after menopause. A total of 208 patients with histologic proven endometriosis were included in this cross-sectional study. Pearson linear correlations with collected data were performed using IBM® Cloud Pack ® For Data and further descriptive statistics was made using IBM® SPSS® v26. The study sample included 6 cases of postmenopausal de novo endometriosis, which represents a 2.88% prevalence. Patients mean age at diagnosis was 56 years [50-79] . Only 16.3% (n = 1) was using menopausal hormone therapy (MHT) and, interestingly, a strong positive correlation was observed between MHT and pelvic pain symptoms (r = 1). Ovarian localization was observed in 83.3% of the sample. Nevertheless, no positive correlation was observed between CA-125 serum values and postmenopausal endometriosis (r = -0.15) comparing to premenopausal women (r = 0.39). The results of this study are in accordance to previous evidence on the subject, highlighting that endometriosis is a rare and poorly understood condition in postmenopausal women. Management of endometriosis in symptomatic menopausal women and risk of malignant transformation remain uncertain. The growing awareness on this topic makes the need for high-quality studies a certainty.