Abstract Study question Does adding letrozole to combined cesarean scar pregnancy (CSP) treatment cause a greater decrease in B-human chorionic gonadotropin (B-hCG) concentrations and less blood loss? Summary answer The addition of letrozole to the combined CSP treatment does not result in a greater decrease in B-hCG concentrations or less blood loss. What is known already There is no reference treatment for CSP as the limited number of cases precludes the extrapolation of results. In our center we successfully use two-step treatment with methotrexate followed by hysteroscopic removal of products of conception (POC). The time in between is needed to achieve a decrease in the trophoblast's vital potential (B-hCG fall) and its vascularization. The suppression of estradiol production by letrozole may interfere with the physiological effect of progesterone, which is essential for the maintenance of pregnancy. Additional administration of letrozole could further reduce the vital potential of the pregnancy, resulting in a lower rate of complications. Study design, size, duration A prospective cohort tertiary single-center study (consent no. 1072.6120.321.2020) was conducted among women with CSP from January 2021 to December 2022. Only women with increasing concentrations of B-hCG and consent of the Bioethics Committee for termination of pregnancy were included. Women with decreasing B-hCG concentrations were excluded. All enrolled women gave informed written consent to participate in the study. Participants/materials, setting, methods All women received a single dose of 100 mg MTX intravenously and 50 mg MTX in intra-amniotic injection (day 0), along with 30 mg potassium chloride in case of positive fetal heartbeat (FH). Women who consented were additionally given letrozole 5 mg orally (day 0) for 10 days. B-hCG concentration was measured on day 0,4,7. After obtaining satisfactory decrease in B-hCG and POC vascularization, women underwent hysteroscopic evacuation of POC. Blood loss parameters were measured. Main results and the role of chance The study included 28 women aged 27-41, with a gestational age of 6-12 weeks. FH was present in 17/28 (60.7%) women. Of the 28 women, 16 (57.1%) received additional letrozole (arm 1). There was no significant difference between arm 1 vs. arm 2 (without letrozole) in terms of gestational age (7.69±1.54 vs. 8.00±2.09 weeks, p = 0.85), FH positivity (10/16, 62.5% vs. 7/12, 58.33%; p = 1), BMI (25.39±5.08 vs. 26.24±6.51; p = 0.82), day 0 B-hCG (47656.89± 37747.87 vs. 51870.83± 45838.87 mIU/ml; p = 0.89) and day 0 hemoglobin (Hb) (12.98±0.74 vs. 12.74±1.26 g/dl; p = 0.57). Timing of hysteroscopy was not significantly different between arm 1 vs. arm 2 (day 22.19± 14.44 vs. 31.42± 25.83; p = 0.42). The dynamics of B-hCG decline in arm 1 vs. arm 2 between days 4-0 (-3295.67± 15133.13 vs. −6883.00± 20029.88 mIU/ml; p = 0.71) and 7-4 (-13137.82± 13765.14 vs. −19145.75± 23526.70 mIU/ml; p = 0.68) was not significantly different. There were no differences between arm 1 vs. arm 2, in decrease in Hb concentration on day 1 post-hysteroscopy (-1.79± 1.67 vs. −2.19± 1.68 g/dl, p = 0.53), blood loss volume (318.75± 437.37 vs. 591.67 ± 744.02 ml; p = 0.29) and rate of hemorrhage (4/16, 25% vs. 3/12, 25% cases, p = 1). Limitations, reasons for caution The limitations of the study are the small sample size, the single-center nature of the study, and the arbitrarily set dosing regimen of letrozole. Wider implications of the findings The results do not support the use of letrozole in the above regimen as an adjunct to combined CSP treatment. Trials with a larger sample size and with a different letrozole dosing regimen are needed to confront the results. Trial registration number 072.6120.321.2020