<p>High ovarian responders are at high risk of developing ovarian hyperstimulation syndrome (OHSS) in in vitro fertilization (IVF). Letrozole administration during the gonadotropin period has the theoretical basis to avoid OHSS. But researches are just beginning. Our prospective cohort study was conducted to explore if the addition of LE are better or not. Totally 107 high responders who received IVF were included, 66 patients for GnRH-ant protocol and 41 patients for co-LE protocol with letrozole combination during gonadotropin period from day 1 to day 5. The IVF outcomes appeared: the clinical pregnancy rate, cumulative pregnancy rate, live birth and ongoing pregnancy rate were both comparable (<i>p</i> &gt; 0.05). Patients in the co-LE group exhibited significantly less gonadotropin dose (1464.39 ± 550.84 vs. 1708.23 ± 455.75, <i>p</i> = 0.015), gonadotropin duration (9.63 ± 2.11 vs. 10.48 ± 1.83&#xa0;days, <i>p</i> = 0.032) and oocytes number (13.29 ± 10.30 vs. 18.18 ± 9.36, <i>p</i> = 0.013). The incidence of early OHSS was significantly lower than that in the GnRH-ant group (0% &amp; 13.6%, <i>p</i> = 0.025). According to our research, the combination of letrozole can improve controlled ovarian stimulation (COS) efficiency and reduce the risk of OHSS while bring effective IVF clinical outcomes equivalent to GnRH-ant regimen for ovarian hyperresponders.</p> Graphic Abstract <p>GnRH-ant: Gonadotropin releasing hormone-antagonist protocol</p> <p>co-LE: GnRH-ant protocol with letrozole combination</p> <p>COS: controlled ovarian stimulation</p> <p>IVF/ICSI: in vitro fertilization/intracytoplasmic sperm injection</p> <p>Conclusion: According to our research, the combination of letrozole can improve controlled ovarian stimulation (COS) efficiency and reduce the risk of OHSS while bring effective IVF clinical outcomes equivalent to GnRH-ant regimen for ovarian hyperresponders.</p> <p></p>