Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein originally identified as a methylated DNA binding protein, which is particularly abundant in mature neurons. Deficiency or excess of MeCP2 causes severe neurological problems. Mutations in MeCP2 account for 95% of the dominant X-linked neurological disorder Rett syndrome. MeCP2 have two key functional domains: the methyl-DNA binding domain (MBD) and the transcriptional repressor domain (TRD). Almost all of missense Rett mutations are clustered in these two domains, such as R133C, F155S, T158M in MBD, and R306H in TRD. The mechanism of the mutations leading to Rett syndrome is still not well understood. Here, we reveal that MeCP2 can drive the liquid–liquid phase separation (LLPS) in complex with DNA. Interestingly, this ability is compromised in the presence of mutations found in Rett syndrome patients, suggesting a potential common mechanism by disrupting LLPS of MeCP2 droplets underlying Rett syndrome.