Disruption of theMECP2gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism1.MECP2encodes a methyl-DNA-binding protein2that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression inMecp2mutants, no clear model has emerged for how MeCP2 protein regulates transcription3,4,5,6,7,8,9. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.