Abstract: Objective: To evaluate the accuracy and false positive rate of congenital heart disease (CHD) screening protocols for early detection of critical CHD (CCHD) in neonates. Methods: Literature search and selection were carried out during the development of the neonatal CCHD screening (NCCHDS) guideline. The reference standard for the diagnosis of CCHD was echocardiography, or through signs and symptoms of neonates during follow-up with confirmation of CCHD by echocardiography, surgery, or cardiac catheterization. The risk of bias and clinical applicability of the included literature were evaluated with the QUADAS-2 scale. Data were extracted and diagnostic parameters including sensitivity and specificity were summarized with the random effect model. Results: Twenty-one articles were included in this meta-analysis, and three different protocols were reported for screening neonatal CCHD: pulse oximetry alone (POX; n=21)，POX+clinical evaluation (CE) (n=3), POX+murmur (MUR) (n=2). The sample size of the included studies ranged from 435 to 167,190. There were 7 studies from the United States, 9 from Europe, 4 from Asia, and 1 from Africa. The sensitivity and specificity of POX alone, POX+CE and POX+MUR screening were 72.2%（95%CI: 60.4%-81.6%）, 91.0%（95%CI: 86.3%-94.2%）and 93.7%（95%CI: 89.2%-96.4%）, respectively and 99.8%（95%CI: 99.7%-99.9%）, 98.5%（95%CI: 96.7%-99.3%）and 98.3%（95%CI: 97.2%-99.0%）, respectively. The AUC was 0.973, 0.964 and 0.982, respectively. Subgroup analysis of POX screening alone showed there were no statistically significant differences in sensitivity across all subgroups (P＜0.01 after correction) and repeated measurement had higher false positive rates compared with single measurement. Heterogeneity of sensitivity and specificity of POX screening for neonatal CCHD was possibly related to whether the screener has been trained, level of hospital, different core technical aspects of screening instruments, and use of reusable or disposable probes or different probe types. Conclusion: The differences among AUC of POX alone, POX+CE, POX+MUR are small. POX alone is available for the moderate sensitivity of screening. POX+CE and POX+MUR are recommended for the higher sensitivity of screening and POX+MUR is recommended for optimizing screening indicators.