Rett syndrome is a neurodevelopmental disease affecting girls. The cause is not known. Roles for trophic factors and excitatory neurotransmitters have beer postulated. To study the significance of excitatory amino acids in Rett syndrome, we determined glutamate and aspartate concentrations in the cerebrospinal fluid from 11 girls with Rett syndrome (age 8 years 4 months ± 5.7 years, mean ± SD) and 11 controls (age 7 ± 4.2 years). In the patients with Rett syndrome, the mean of cerebrospinal fluid glutamate concentration was 355.2 nmol/L (SD ± 109.2 nmol/L). In the controls it was 203.9 nmol/L (SD ± 55.5 nmol/L). In Rett syndrome cases, cerebrospinal fluid glutamate concentrations were significantly higher (P = 0.0006) than in the controls. In the Rett syndrome group, the mean cerebrospinal fluid aspartate concentration was 119.4 nmol/L (SD ± 43.5 nmol/L). In the control group, it was 90.9 nmol/L (SD ± 20.9 nmol/L). The difference between the cerebrospinal fluid aspartate values was not significant. Glutamate may therefore play an important role in the primary pathogenesis in Rett syndrome. Further investigations are needed, with recognition of possible actions of neuronal growth factors and excitatory neurotransmitters in the damage mechanisms of Rett syndrome.