OBJECTIVE: Although cell-free DNA screening for sex chromosome abnormalities is increasingly used in clinical practice, its diagnostic accuracy and clinical utility remain unclear. This systematic review and meta-analysis aimed to determine the performance of cell-free DNA in the detection of sex chromosome abnormalities. DATA SOURCES: Medline and PubMed, Embase, and Web of Science were searched from inception to January 2022 for articles relating to cell-free DNA screening for sex chromosome abnormalities. STUDY ELIGIBILITY CRITERIA: Original articles, randomized control trials, conference abstracts, cohort and case-control studies, and case series with more than 10 cases with diagnostic confirmation were considered for inclusion. METHODS: Quality assessment of each included publication was performed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. The positive predictive value was calculated as the proportion of true positive cases among those who tested positive and underwent diagnostic testing. Sensitivity and specificity were pooled, and a summary receiver operating characteristic curve was produced using bivariate models that included studies that had diagnostic confirmation for high- and low-risk women. RESULTS: The search identified 7553 results. Of these, 380 proceeded to the full-text screening, of which 94 articles were included in the meta-analysis with a total of 1,531,240 women tested. All studies reported a confirmatory genetic test. The pooled positive predictive value was 49.4% (95% confidence interval, 45.8–53.1). The pooled positive predictive value was 32.0% (95% confidence interval, 27.0%–37.3%) for monosomy X, 67.6% (95% confidence interval, 62.5%–72.5%) for XXY, 57.5% (95% confidence interval, 51.7%–63.1%) for XXX, and 70.9% (95% confidence interval, 63.9%–77.1%) for XYY. The pooled sensitivity and specificity of cell-free DNA for sex chromosome abnormalities were 94.1% (95% confidence interval, 90.8%–96.3%) and 99.5% (95% confidence interval, 99.0%–99.7%), respectively, with an area under the summary receiver operating characteristic curve of 0.934 (95% confidence interval, 0.907–0.989). CONCLUSION: Although the sensitivity and specificity of cell-free DNA for sex chromosome abnormalities are high, the positive predictive value was approximately 50%. The positive predictive value was higher for sex chromosome abnormalities with a supernumerary Y chromosome and lower for monosomy X. Clinicians should inform couples about these findings when offering cell-free DNA for sex chromosome abnormalities.