Objectives: Endometrial preparation provides significant surgical benefits prior to hysteroscopic procedures. However, there is still no consensus on the optimal presurgical protocol. Although there is evidence on rapid preparation, there are currently no studies on rapid endometrial preparation using combined oral contraceptives initiated at a "random" time in the menstrual cycle. The aim of the present trial was to evaluate the use of oral drospirenone/estetrol in random start rapid preparation of endometrium before office hysteroscopic polypectomy. Design: In this multicenter, prospective, randomized controlled trial, 80 women scheduled for polypectomy were randomly assigned to intervention (n = 40) or control (n = 40) groups. Participants/Materials, Setting, Methods: The intervention group received oral drospirenone/estetrol (3 mg/14.2 mg/day) for 14 days, starting at any menstrual cycle point (random start). Controls underwent polypectomy on cycle days 8-11 without any prior pharmacological intervention. Results: Pre- and post-procedure, endometrial thickness was significantly lower in the drospirenone/estetrol group (p < 0.001), and patients showed more hypotrophic/atrophic endometrial patterns (p < 0.001). Operative time, distension medium usage, incomplete resections, and bleeding during polypectomy were significantly lower in the drospirenone/estetrol group (p < 0.001). Endometrial preparation quality, uterine cavity visualization, and procedure satisfaction were higher in the drospirenone/estetrol group (p < 0.001). Furthermore, patients in the drospirenone/estetrol group experienced less pain during (p < 0.001) and after the procedure (p < 0.001), requiring fewer analgesics (p < 0.001) and shorter post-procedure discharge time (p = 0.01) than controls. Limitations: Limited sample size; possible variability due to different hysteroscopists, caused by the multicenter nature of the study; hysteroscopists were unmasked to treatment allocation; absence of a cost-effectiveness analysis. Conclusions: Treatment with drospirenone/estetrol could provide rapid, satisfactory and low-cost endometrial preparation before office polypectomy, improving surgical performance and patient compliance.