BackgroundTo explore and compare the clinical effects of high‐resolution non‐invasive prenatal screening (NIPS‐Plus) for common/uncommon chromosomal aneuploidy and microdeletion/microduplication syndromes (MMS).MethodsThe current prospective study included a total of 25,380 pregnant women who performed NIPS‐Plus, and amniocentesis was performed on women with MMS with the screening results to diagnose patients with suspected MMS.ResultsThere were 415 samples with positive results for NIPS‐Plus, included 275 with aneuploidy and 140 with MMS. After diagnosis by amniocentesis, 188 cases were confirmed as true positive, included46 cases of T21, 9 cases of T18, 1 case of T13, 34 cases of SCA, 41 cases of other chromosomal euploidy and 57 cases of MMS. In addition, no false negative cases were found, MMS was classified with 5 Mb with the cutoff value, and the PPV of different fragment size was counted, respectively.ConclusionWe found that the corresponding PPV was 44.66% with the fragment of copy number variation (CNV) being less than or equal to 5 Mb, and when it was greater than 5 Mb, the PPV was 29.73%, which suggested that NIPS‐Plus was more suitable for screening the PPV of small fragment abnormalities. NIPS‐Plus has a good application effect in routine aneuploidy screening and had the best detection effect for T21; moreover, it performed well in screening of MMS and had better detection effect on MMS with CNV fragment length less than 5 Mb. Based on the current results, we suggested that NIPS‐Plus should be used as a comprehensive elementary prenatal screening method for all pregnant women, but for MMS caused by abnormal large fragment CNV, the detection method and efficiency still need to be improved.