Research questionDoes endometrial preparation using a natural cycle (NC) lead to higher live birth rates (LBR) in single euploid frozen embryo transfers (seFET) compared to programmed cycles (PC), for women across normal, overweight, and obese body mass index (BMI) categories? DesignRetrospective study of 845 seFETs. Patients were stratified by BMI into 3 categories (Normal weight, Overweight, and Obesity Class I/II). Outcome was LBR. ResultsA total of 845 seFET cycles of 688 couples were included in the analysis. After achieving covariate (female age, AMH, embryo quality and infertility type) balance in each stratum, the effective sample size was 481 and 262 for the PC and NC, respectively. The PC approach, in which patients received vaginal luteal phase support with 3×100 mg micronized vaginal progesterone (MVP)/day, were associated with significantly lower LBR in the weighted regression analysis of the cohort (RR: 0.80, 95%CI: 0.73 – 0.88, p<0.001), compared to the NC approach. The effect was significantly modified by BMI (P=0.003). While the effect was significant for all BMI categories, the reduction in live birth was less pronounced in patients with normal or overweight BMI (RR: 0.87, 95%CI: 0.78-0.97, p=0.014) compared to patients with class I/II obesity (RR: 0.61, 95%CI: 0.49-0.75, p<0.001). ConclusionA natural cycle endometrial preparation approach leads to overall better live birth rates in single euploid FET, and the most significant difference is observed in women with higher BMI. Furthermore, overweight / obese patients in a PC may require a higher dosage of progesterone for luteal phase support.