Abstract Study question Frozen euploid single blastocyst transfer in modified natural cycle (mNC) increases success rates, improving obstetric outcomes compared to hormone replacement therapy (HRT) protocols? Summary answer Elective euploid single-blastocyst transfer (eeSBT) in mNC did not show higher success rates nor better obstetric and perinatal outcomes compared to HRT protocols What is known already eeSBT has become the gold standard for clinical trials in assisted reproduction, increasing sample homogeneity and reducing bias; when choosing endometrial preparation protocols for thawed embryo transfers, recent clinical studies have reported the superiority of mNC over HRT in terms of delivery and miscarriage rates, obstetrical and perinatal outcomes, treatment safety and costs; however, few data are available on eeSBT ≥3BB (Gardner score) cryotransfers comparing both protocols Study design, size, duration Retrospective single-centre comparative clinical study, including 1.354 eeSBT (≥3BB, Gardner score) between Jan-2018 and Dec-2022: 1.109 (82%) in HRT and 245 (18%) in mNC. HRT and mNC groups were homogeneous for egg donor’s age (28,9±5,8 yo Vs 30,6±5,9 yo), recipient’s age (41,7±5,0 yo Vs 39,5±4,5 yo), body mass index (22,6±4,8 Vs 23,1±3,4) severe male factor (3,5% Vs 7,3%), the need for sperm donation (30,4% Vs 27,8%), and the average throphoectoderm embryo quality (A = 32,1% Vs A = 31,8%) Participants/materials, setting, methods We studied the clinical, obstetric and perinatal outcomes of the 1.354 eeSBT performed, comparing HRT and mNC cycles for: pregnancy rate, miscarriage rate, live birth rate, twin pregnancy rate, severe preeclampsia, preterm birth rate (<37, <35, <32 and <28 weeks) and neonatal weight. We used Chi-square test to compare groups (p < 0,05). Main results and the role of chance There were no statistically significant differences between HRT Vs mNC protocol when comparing pregnancy rates (63,8% Vs 62,0%, p = 0,61), miscarriage rates (15,3% Vs 15,8%, p = 0,87) and live birth rates (44,6% Vs 46,1%, p = 0,67). The were no twin pregnancies in the mNC group, and only 5 (1%) in the HRT group. There we no significant differences in the severe preeclampsia rate, even if it doubled in the HRT group compared to mNC (1,8% Vs 0,9%, p = 0,48). Preterm, major and extreme preterm birth rates were higher in HRT but comprable to the mNC group: <37 weeks (7,7% Vs 6,2%, p = 0.59) < 35 weeks (2,8% Vs 1,8%, p = 0,59) <32 weeks (1,2% Vs 0,9%, p = 0,77) <28 weeks (0,4% Vs 0,9%, p = 0,51). There were no significant differences in neonatal weight (3287 + 477g HRT Vs 3271 + 512g in mNC, p = 0,88). Limitations, reasons for caution The HRT group included 84 patients in menopause (confounding factor), but when excluding them in a preliminary study results didn’t change. We decided to include eeSBT both from egg donation and own patient’s egg IVF treatments, after verifying that there were no significant differences in clinical results between both groups. Wider implications of the findings In eeSBT, the use of modified natural cycle could be encouraged because of its better cost-effectivenes and patient’s comfort. This study reports a non-significant trend for higher success rates in mNC compared to HRT; further prospective trials should be promoted to give accurate advice to patients undergoing thawed embryo transfers. Trial registration number Not Applicable