Since 1925, epidemiological and histological evidence for an association between endometriosis and ovarian neoplasia has accumulated. Recently, publications assaying the clonality of a given cell population have implied endometriosis has premalignant properties. However, the human androgen receptor used as a marker in these studies is of highly questionable reliability due to the instability of its methylation pattern in nonmalignant cells and during the course of malignancy. Therefore, we decided to readdress the question of clonality of endometriotic foci by using an alternative assay based on a polymorphism of the phosphoglycerate kinase-1 gene. We overcame the limitation to using ovarian cysts (a problem encountered in other studies) by laser-microdissecting defined tissue fractions of interest. From the 13/29 informative patients, a total of 32 endometriotic samples from various sites was assayed. Only 2/32 samples from different patients bore monoclonal tissue. With one of those cases, we present the first direct evidence of the two morphological endometric compartments comprising a single biphasic developmental unit. Neither monoclonal patient was characterized by any outstanding clinical parameters, including neoplasia. Individual endometriotic foci from the only patient in this study with neoplasia was assayed as being polyclonal. Therefore, former studies stating endometriosis as premalignant have to be cautiously reinterpreted.