<h4>Objective</h4>This study aimed to synthesize available high-quality randomized controlled trials (RCTs) comparing reproductive outcomes between letrozole (LE) and clomiphene citrate (CC) for ovulation induction in women with PCOS.<h4>Methods</h4>Following PRISMA guidelines, this review was registered in PROSPERO (CRD420251013416). A comprehensive search was conducted in PubMed, Cochrane Library, Elsevier, the National Library of Medicine, and Google Scholar up to March 2025. A total of 32 RCTs were included. Statistical analysis used a random-effects model to calculate risk ratios (RR) with 95% confidence intervals (CI), as determined using Review Manager. Heterogeneity was assessed with the I2 statistic. The risk of bias was evaluated using the ROB 2 tool. The primary outcome was ovulation rate; secondary outcomes included pregnancy, live birth, miscarriage, and multiple pregnancy rates.<h4>Results</h4>LE showed higher ovulation (RR: 1.18; 95% CI: 1.11-1.25; I2: 57%) and pregnancy rates (RR: 1.57; 95% CI: 1.39-1.76; I2: 21%) compared to CC. LE also had a higher live birth rate (RR: 1.54; 95% CI: 1.24-1.91; I2: 35%). Miscarriage rates were similar between groups (RR: 0.97; 95% CI: 0.73-1.28; I2: 0%). The multiple pregnancy rate was significantly lower in the LE group (RR: 0.42; 95% CI: 0.18-0.98; I2: 0%).<h4>Conclusions</h4>Letrozole shows greater effectiveness than clomiphene citrate for ovulation induction in women with PCOS, with a lower risk of multiple pregnancy and similar miscarriage risk. These findings support its use as a first-line treatment in clinical practice. ORCID: https://orcid.org/0009-0006-0640-4040 , Email: katherinereimao000@gmail.com Jan-Feb 2026 Jan-Feb 2026 30 1 511154 146 159 15 4 2025 25 10 2025 01 01 2026 08 04 2026 08 04 2026 https://creativecommons.org/licenses/by/4.0/ This is an Open Access Results LE showed higher ovulation (RR: 1.18; 95% CI: 1.11-1.25; I 2 : 57%) and pregnancy rates (RR: 1.57; 95% CI: 1.39-1.76; I 2 : 21%) compared to CC. LE also had a higher live birth rate (RR: 1.54; 95% CI: 1.24-1.91; I 2 : 35%). Miscarriage rates were similar between groups (RR: 0.97; 95% CI: 0.73-1.28; I 2 : 0%). The multiple pregnancy rate was significantly lower in the LE group (RR: 0.42; 95% CI: 0.18-0.98; I 2 : 0%). Conclusions Letrozole shows greater effectiveness than clomiphene citrate for ovulation induction in women with PCOS, with a lower risk of multiple pregnancy and similar miscarriage risk. These findings support its use as a first-line treatment in clinical practice. polycystic ovary syndrome PCOS ovulation induction letrozole clomiphene citrate infertility pmc-status-qastatus 0 pmc-status-live yes pmc-status-embargo no pmc-status-released yes pmc-prop-open-access yes pmc-prop-olf no pmc-prop-manuscript no pmc-prop-legally-suppressed no pmc-prop-has-pdf yes pmc-prop-has-supplement no pmc-prop-pdf-only no pmc-prop-suppress-copyright no pmc-prop-is-real-version no pmc-prop-is-scanned-article no pmc-prop-preprint no pmc-prop-in-epmc yes pmc-license-ref CC BY INTRODUCTION Polycystic ovary syndrome (PCOS) is a chronic and heterogeneous endocrine disorder that affects between 8-20% of women of reproductive age each year. CC lowers hypothalamic ERs, making circulating estrogen seem low, which prompts the body to compensate by changing gonadotropin-releasing hormone (GnRH) secretion. This results in increased release of pituitary gonadotropins, which stimulate ovarian follicle growth. However, in 2023, new recommendations for PCOS treatment were included in the international evidence-based guideline for assessing and managing PCOS, published in the Fertility and Sterility Journal ( Teede et al ., 2023 ). These guidelines show that letrozole (LE), an aromatase inhibitor, has been accepted as the new first-line medication for ovulation induction in women with PCOS and anovulatory infertility. This meta-analysis included only randomized controlled trials (RCTs) comparing LE versus CC alone, used for ovulation induction in women with PCOS, and reporting at least one of the outcomes included in this meta-analysis. Inclusion criteria were women aged 18 to 40 years old, diagnosed with PCOS according to the Rotterdam criteria ( Rotterdam, 2004 ), presenting at least two of three variables: oligo-ovulation and/or anovulation; clinical or biochemical signs of hyperandrogenism; and polycystic ovaries confirmed by ultrasound, having more than 12 follicles smaller than 10 mm in diameter or increased ovarian volume greater than 10 cm 3 in one or both ovaries, and at least one patent fallopian tube confirmed via HSG. Only studies investigating ovulation induction in natural menstrual cycles were included. Unlike some older meta-analyses that failed to show significant differences, likely due to smaller population sizes or variations in outcome reporting, this review benefits from a larger and more diverse data set, leading to clearer and more dependable conclusions. From a clinical perspective, letrozole seems to offer several benefits over clomiphene citrate. Its higher rates of ovulation, pregnancy, and live birth, combined with a significantly lower risk of multiple pregnancy, make it a strong choice for first-line treatment in women with PCOS. Multiple pregnancies carry increased risks for both mother and baby. Future research should include more diverse populations to enhance generalizability. More studies comparing different dosing protocols and examining long-term outcomes, especially regarding child health, would also help guide safer and more effective clinical practices. CONCLUSION This systematic review and meta-analysis demonstrates that LE is more effective than CC in several key clinical outcomes related to the treatment of infertility in women with polycystic ovary syndrome (PCOS). LE was consistently associated with a higher likelihood of ovulation, clinical pregnancy, and live birth, as well as a lower risk of multiple pregnancy compared to CC.