To estimate the effect of letrozole and clomiphene citrate in women with infertility and polycystic ovarian syndrome (PCOS).MEDLINE through PubMed, Web of Science, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched for relevant studies from inception to February 1, 2022. Two reviewers retrieved, filtered, and extracted data independently using the bibliographic software EndNote X9 and Excel workbook. We included randomized controlled trials (RCTs) reporting ovulation induction outcomes in women with infertility and PCOS treated with either letrozole or clomiphene citrate followed by timed intercourse or intrauterine insemination. The data were merged into a mean difference or risk ratio (RR) with 95% CI, depending on variable types.Data collection and organization were conducted in accordance with the 2020 PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Twenty-nine RCTs were eligible, which included 3,952 women and 7,633 ovulation induction cycles. We acquired evidence from 22 RCTs for the ovulation rate, 28 RCTs for the clinical pregnancy rate, and eight RCTs for live-birth rate. Pooled analysis indicated that letrozole treatment prevailed against clomiphene citrate in ovulation rate (RR 1.14, 95% CI 1.06-1.21, P <.001), clinical pregnancy rate (RR 1.48, 95% CI 1.34-1.63, P <.001), and live-birth rate (RR 1.49, 95% CI 1.27-1.74, P <.001).Letrozole was associated with improved ovulation, pregnancy, and live-birth rates compared with clomiphene citrate. We recommend letrozole over clomiphene citrate as an ovulation induction drug in women with infertility and PCOS, although the quality of the evidence is mixed.PROSPERO, CRD42022308777.Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.