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. Periodic breathing (Cheyne-Stokes respiration) is commonly seen in RTT. Freely moving mice were studied with continuous recording of pleural pressure by telemetry. Episodes of periodic breathing in heterozygous Mecp2 deficient female mice (9.4 ^± 2.2 hr ^-1) exceeded those in wild type animals (2.5 ± 0.4 hr ^-1) (p=0.010). Exposing Mecp2^+/- animals to 40% oxygen increased the amount of periodic breathing from 118 ^± 25 s 30 min ^-1 in air to 242 ^± 57 s 30 min ^-1 (p=0.001) and 12% oxygen tended to decrease it (67 ^± 29 s 30 min^-1, p=0.14). Relative hyperoxia and hypoxia did affect the incidence of periodic breathing in Mecp2^+/+ animals. The ventilation/apnea ratio (V/A) was less at all levels of oxygen in heterozygous Mecp2 deficient females compare to wild type (P=0.003 to <0.001), indicating that their loop gain is larger. V/A in Mecp2 ^+/- fell from 2.42 ^± 0.18 in normoxia to 1.82 ^± 0.17 in hyperoxia (p=0.05) indicating an increase in loop gain with increased oxygen. Hyperoxia did not affect V/A in Mecp2 ^+/+ mice (3.73 ± 0.28 vs 3.5 ± 0.28). These results show that periodic breathing in this mouse model of RTT is not dependent on enhanced peripheral chemoreceptor oxygen sensitivity. Rather, the breathing instability is of central origin.