Abstract Study question Could personalized regenerative medicine based strategies promote endometrial growth and receptivity in women with refractory thin endometrium resulting in successful implantation and live births? Summary answer Personalized regenerative medicine based strategies remarkably promote endometrial growth and receptivity in women with refractory thin endometrium resulting in successful implantation and live births. What is known already Repeated implantation failure (RIF) due to thin endometrium is a formidable challenge in reproductive medicine, often steering couples toward the stressful option of surrogacy. Regenerative approaches like platelet-rich plasma (PRP) have shown promise, leveraging the anti-inflammatory and pro-regenerative properties of platelet-derived growth factors. Recognizing the need for an anti-inflammatory milieu for successful implantation, Endosera, a cell-free implantation-friendly growth factors concentrate, has been developed. This study at Bloom IVF Centre-Mumbai, India, aims to assess Endosera’s efficacy in enhancing endometrial thickness and implantation rates, providing potential solutions for RIF and thin endometrium. Study design, size, duration In this prospective self-controlled study 72 women (27-49 years) were enrolled spanning December 2022 to December 2023. Women experienced two or more failed IVF cycles and multiple cycle cancellations due to refractory thin endometrium, negative hysteroscopic screening for endometrial pathology, and negative bacteriologic screening and despite multiple failed conventional therapies were selected to undergo Endosera treatment. Participants/materials, setting, methods After obtaining informed consent, patients underwent three intrauterine infusions of Endosera on menstrual cycle Day 7, Day 12, and 2 days before frozen embryo transfer (FET). Alongside standard hormone replacement therapy (HRT), Endosera was introduced into the uterine cavity. Pregnancy confirmation relied on a positive serum β-HCG test two weeks post-ET, while clinical pregnancy was established by detecting fetal heartbeat through transvaginal ultrasound four weeks post-ET. Main results and the role of chance In this study involving 72 patients facing recurrent implantation failure due to refractory thin endometrium, the administration of three doses of Endosera demonstrated significant positive outcomes. The average endometrial thickness notably increased from 6.4 ± 1.1 mm to 8.7 ± 1.0 mm (P < 0.0001) after the 2nd Endosera dose, reaching an optimal thickness of ≥ 7mm. Among the participants, 34 achieved a positive pregnancy result (47.2%), with 6 (8.3%) delivering healthy babies and 23 (31.9%) experiencing ongoing clinical pregnancies. Adverse outcomes included 2 (2.8%) ectopic pregnancies and 3 (4.2%) miscarriages before 10 weeks, while 36 (50%) women returned negative HCG results. No adverse effects were reported, indicating the safety of Endosera. The formulation, standardized to contain 6-9 times higher growth factor levels than peripheral blood, emphasizes implantation-friendly and anti-inflammatory cytokines. This optimized composition aligns with the cyclical requirements of the endometrial phases (proliferation, secretion, and implantation), creating an angiogenic and anti-inflammatory environment crucial for successful implantation. Endosera’s safety, reproducibility, and efficacy in mimicking natural tissue repair and regeneration processes position it as a promising solution for refractory thin endometrium-related challenges. Limitations, reasons for caution This study, though demonstrating improved outcomes in refractory thin endometrium cases with Endosera treatment, acknowledges limitations such as small sample size and absence of a randomized control group. To establish Endosera as a routine adjuvant in IVF, a larger study with stringent inclusion criteria for refractory thin endometrium is recommended. Wider implications of the findings Endosera demonstrated notable success with significant improvement in implantation, pregnancy, and live birth rates for refractory thin endometrium patients prompts rigorous randomized controlled studies. These will include diverse populations, validating results and offering patients hope to reduce financial and psychological stress and challenges associated with cycle cancellations and surrogacy. Trial registration number Not applicable