OBJECTIVE: To evaluate the performance of prenatal cell-free DNA (cfDNA) screening with and without the cell-free fetal DNA enrichment method in general-risk and high-risk pregnancies. METHODS: We performed a size-selective cell-free fetal DNA enrichment in 71,986 pregnancies. The cfDNA screening and follow-up results were collected for trisomies 21, 18, 13, fetal sex chromosome abnormalities (SCAs), and copy number variants (CNVs). The fetal fraction of cfDNA, positive rates, and positive predictive values (PPV) were compared between the general-risk and high-risk pregnancies with and without enrichment. RESULTS: With the cell-free fetal DNA enrichment, the fetal fraction of cfDNA increased to 18.87 ± 5.94. The overall PPVs for common trisomies increased to 88.46% and 91.11% in the general- and high-risk populations, respectively. For CNVs, the PPVs with enrichment increased to 53.52% and 66.67% in the general risk and high-risk populations, respectively. However, for SCAs, the PPV was not improved by cell-free fetal DNA enrichment. The failure rates in the general-risk and high-risk groups decreased to 0.01% and 0.08%. CONCLUSIONS: Cell-free fetal DNA enrichment significantly improves the PPVs of common trisomies and CNVs in general and high-risk populations. It has the potential for the clinical application effect of cell-free DNA screening.