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 (Mecp2^+/−) female mice (9.4 ± 2.2 h⁻¹) exceeded those in wild-type (Mecp2^+/+) animals (2.5 ± 0.4 h⁻¹) (P = 0.010). Exposing Mecp2^+/− animals to 40% oxygen increased the amount of periodic breathing from 118 ± 25 s/30 min in air to 242 ± 57 s/30 min (P = 0.001), and 12% oxygen tended to decrease it (67 ± 29 s/30 min, P = 0.14). Relative hyperoxia and hypoxia did not 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^+/− females compare with wild type (P = 0.003 to P < 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.