Introduction: This study was performed to assess the optimal resolution for prenatal testing by array comparative genomic hybridization (aCGH), aiming to balance between maximum diagnostic yield and minimal detection of variants of uncertain significance (VOUS). Methods: This was a prospective study using data of 2,336 fetuses that underwent invasive prenatal diagnosis, and the samples were analyzed by aCGH. In total, six different aCGH platforms were studied; four different resolutions (0.18 Mb, 0.5 Mb, 1 Mb, and 2 Mb) and two platform designs (whole-genome [WG] and targeted). The results of these designs were compared based on their diagnostic yield and VOUS rate. The performance of the different designs was further analyzed according to indication for invasive testing. Results: The diagnostic yield of copy number variants increased with increasing level of analysis. The detection rates of clinically significant chromosomal abnormalities were almost the same across our targeted array designs; 7.2% with 0.18 Mb backbone/0.05 Mb versus 7.1% with 0.5 Mb backbone/0.05 Mb (p >0.05). However, a significant difference in the rate of VOUS was observed; 9.4% with 0.18 Mb backbone/0.05 Mb versus 6% with 0.5 Mb backbone/0.05 Mb (p <0.001). After analyzing the results across different indications for testing, we found that the application of non-targeted platform designs and lower levels of resolution analysis (such as 1 Mb WG or 0.5 MbL/1 MbG WG) would offer similar diagnostic yield in most cases with major congenital anomalies, with lower VOUS rates. However, the sample size for many indication groups was too small to extract robust associations. Conclusion: It appears that the targeted array platform with 0.5 Mb backbone resolution and 0.05 Mb on targeted gene-rich regions is optimal for routine chromosomal microarray analysis use in prenatal diagnosis. It may be beneficial to individualize the minimum resolution in specific referral indications as the indications for invasive prenatal testing may be quite heterogeneous.