High-dose progestins are used as an effective therapy for painful symptoms of endometriosis but their impact on sexual function has been poorly studied. The study aims to assess the impact of high-dose progestin on sexual function among women treated for endometriosis. In this bicenter prospective observational study, women with endometriosis who received medical or surgical treatment for endometriosis and who were sexually active were included. They completed the Sexual Activity Questionnaire (SAQ, a validated tool) before (T0) and 12 months after (T1) endometriosis treatment. We classified patients into two groups according to whether they were using high-dose progestins at T1: a high-dose progestin group and a control group. The main outcome was sexual function measured by the SAQ score (from 0 to 30) at T1. The secondary outcomes were each individual SAQ item, the dyspareunia 100-mm visual analog scale (VAS) and the quality of life assessed with EuroQoL Group 5D Index (EQ-5D) at T1. We also assessed the change in dyspareunia VAS and quality of life between T0 and T1. The Ethics Committee of Ile-de-France (Act 2004-806, 9 August 2004) approved the study. Among 214 women included, 25 (12%) were exposed to high-dose progestins at T1. The SAQ score of women exposed to high-dose progestins was significantly lower compared with the control group, with or without adjustment for covariates (15.5 ± 6.3 vs 18.3 ± 6.2, P = .03, adjusted effect size -0.44 [95% CI -0.86 to -0.02], P = .04). High-dose progestin intake at T1 was associated with a lower subscore on two SAQ items: pleasure (1.8 ± 0.8 vs 2.2 ± 0.9, P = .02), and satisfaction with frequency of intercourse (1.2 ± 1.2 vs 1.8 ± 1.1, P = .02). In the overall population, dyspareunia VAS and quality of life assessed by EQ-5D improved between T0 and T1 (45 ± 29 at T0 vs 28 ± 29 at T1, P < .001; 0.78 ± 0.14 at T0 vs 0.86 ± 0.14 at T1, P < .001, respectively). At T1, the groups did not differ significantly for dyspareunia VAS (effect size 0.36 [95% CI -0.06 to 0.78], P = .10) and quality of life (EQ-5D, effect size 0.02 [95% CI -0.40 to 0.44], P = .91). In this observational study, high-dose progestins impair the sexual function of women treated for endometriosis even though they improved dyspareunia. © 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.