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Endometriosis is a chronic systemic disease affecting 1 in 10 people assigned female at birth, that can result in appearance-based and functional bodily changes which can negatively impact body image. Empirical evidence supports the body dissatisfaction-driven hypothesis that negative body image leads to greater depressive symptoms; but potential underlying mechanisms are under-researched. This prospective study investigated the mediating role of two theoretically-derived intervening factors, self-esteem and rumination, in individuals living with endometriosis who typically report high rates of body image concerns and depressive symptoms. Initially, 996 participants completed the first online survey (T0) assessing demographic, medical and psychological factors. Of these, 451 completed surveys at 1-month (T1) and 2-months (T2) follow-up assessing self-esteem, rumination and depression. Bootstrapped analyses with full-information maximum likelihood estimation indicated that poor body image (T0) predicted greater depressive symptoms over time (T2). Self-esteem (T1), but not rumination (T1), mediated the body image-depression relationship. These results provide support for the body dissatisfaction-driven hypothesis and further identify that self-esteem is a key meditating factor. This highlights the importance of addressing self-esteem in body image focused interventions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)