Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) that encodes a DNA binding protein involved in gene silencing. Selective deletion of Mecp2 in post-mitotic neurons in mice results in a Rett-like phenotype characterized by disturbances in motor activity and body weight, suggesting that these symptoms are exclusively caused by neuronal deficiency. Included in the RTT phenotype are episodes of respiratory depression that follow hyperventilation. Here we show that the respiratory phenotype depends on the organ distribution of Mecp2 deficiency. Both female mice heterozygous for a null mutation in Mecp2 (Mecp2+/-) and those with selective deletion of the protein in neurons (Mecp2+/nestin-Cre lox), showed an initial response to hypoxia that exceeded that in wild type (WT). However, marked respiratory depression following hypoxic hyperventilation was only seen in Mecp2+/- animals. Addition of carbon dioxide to the hypoxic exposure eliminated the respiratory depression. Tidal volume and lung volume were larger in Mecp2+/- and respiratory depression was directly related to tidal volume. Taken together these results indicate that the depression is due to hypocapnia. Respiratory depression in this mouse model of Rett Syndrome is seen in with ubiquitous deficiency in Mecp2 but not when it is confined to neurons.