<p>This study aims to examine the relationship between early-to-mid-luteal estradiol levels and outcomes in hormone replacement therapy-frozen embryo transfers. A systematic search of PubMed, Scopus, Embase, and Web of Science databases was conducted on September 14, 2024, for peer-reviewed studies comparing early-to-mid-luteal serum estradiol levels in women achieving versus not achieving pregnancy following hormone-replacement therapy-frozen embryo transfer. The primary outcomes included biochemical, clinical, ongoing pregnancy, and live birth. A random-effects meta-analysis was planned to compare estradiol levels between groups. Twelve studies encompassing 4,941 cycles were included. No significant early-to-mid-luteal estradiol differences were reported for biochemical (two studies), clinical (six studies), ongoing pregnancy (two studies), or live birth outcomes (four studies). Eleven studies had favorable quality in our risk of bias assessments. Meta-analysis revealed lower estradiol levels in cycles resulting in clinical pregnancy versus those without (six studies; 2,178 cycles; Hedges’s g = -0.151 [-0.289, -0.013]; <i>p</i> = 0.032). Additionally, cycles resulting in live births had lower estradiol levels compared to those not resulting in live births (three studies; 2,169 cycles; Hedges’s g = -0.235 [-0.330, -0.141]; <i>p</i> &lt; 0.001). Our findings suggested that elevated early-to-mid-luteal serum estradiol levels may impair the outcomes of hormone replacement therapy-frozen embryo transfers. Therefore, monitoring serum estradiol during hormone replacement therapy cycles may help optimize estrogen administration to maintain physiological levels, improving outcomes. However, our analysis was limited by few studies and variability, highlighting the need for further research.</p>