Abstract Study question Is there any difference in outcome of frozen embryo transfer(FET) between hormone replacement therapy(HRT) and modified natural cycle(MNC) in previously cancelled true natural cycle patients Summary answer In patients with previous history of cancelled true natural cycle, MNC results in higher clinical pregnancy rates after FET, when compared to HRT cycle What is known already Preparation of endometrium lays down the foundation for conception and subsequent successful pregnancy.There has been a plethora of endometrial preparation protocols described in the literature. The established protocols are true natural cycle,MNC with or without luteal phase support(LPS) and HRT cycle with or without gonadotrophin releasing hormone agonist(GnRha) suppression. Nevertheless,there is no consensus on protocol which may provide the best outcome in patients who have had cancelled true natural cycle.In such situations,HRT cycle may be considered as an easy option as the cancellation rate is low.However,HRT treatment is known for higher early pregnancy and obstetric complications,compared to MNC Study design, size, duration Prospective observational study,where 155 patients undergoing FET who had minimum one true natural cycle cancellation were recruited.They were divided into group A undergoing HRT cycle(n = 77) and group B for MNC cycle(n = 78).The study was conducted in a fertility unit over six months from June-November 2023.Primary outcome measures were serum betaHCG estimation and ultrasonographic documentation of intrauterine pregnancy.Results were analysed using statistical software SPSS version25 and p value of less than 0.05 was considered statistically significant Participants/materials, setting, methods HRT patients received injectable GnRha 3.75 mg on day21 of previous cycle.Oral estradiol valerate 6mg daily started on day2 of menses. When ET was minimum 7mm, luteal phase support(LPS) was started with daily oral and vaginal progesterone(30mg and 600mcg respectively),followed by FET. MNC patients received Letrozole 5mg daily from day 2-6 of menstruation.rhCG 250mcg was given subcutaneously,when ET was at least 7mm,dominant follicle 16-18mm and progesterone(P4) less than 1ng/ml.LPS(vaginal progesterone600mcg) was started 36hours after rHCG,followed by FET Main results and the role of chance Mean ET in MNC group was 8.92mm ± SD1.38, which was higher than HRT group (8.31 mm ± SD0.89). This difference was statistically significant with a p value of 0.014.Serum beta HCG estimation was done 2weeks after FET. In HRT group beta HCG was positive in 41 out of 77(53.25%) and in MNC group positivity was higher being 48 out of 78(61.54%). However, this difference was not statistically significant. Transvaginal ultrasonography(TVS) was done to confirm intrauterine pregnancy 2weeks after beta HCG assay. Clinical pregnancy rate(CPR) was higher in MNC group with 32 out of 78(41.03%),compared to 18 out of 77(23.38%) in HRT group. This difference is statistically significant with p value of 0.019 Limitations, reasons for caution Relatively small population in this study may be the reason for caution to interpret the statistical data. Study with higher numbers may bring about more robust conclusions Wider implications of the findings Patients with failed true natural cycles may be considered for modified natural cycle(MNC) stimulation for FET, without attempt of another true natural cycle stimulation Trial registration number NOT APPLICABLE