Rett syndrome (RTT) is a rare neurodevelopmental disorder, linked to MECP2 gene mutations in the majority of cases, which results in severe disability and is associated with several comorbidities. The clinical condition of RTT patients tends to stabilize over time, and prolonged survival has recently been demonstrated. However, limited information is available on the long-term course of older patients with RTT, especially among those in Southern Europe. The aim of our study is to evaluate the main clinical features and state of health of adult Italian patients with RTT and to present their evolution over time, identifying major clinical issues present at different ages. A total of 130 families of patients with RTT aged ≥14 years were asked to complete a questionnaire, 84 of which were returned (65%). Among the clinical characteristics of RTT, stereotypies and poor hand function and feeding ability remained stable over time, while nonverbal communication tended to improve. With regard to the main pathologies, sleep, behavioral, and autonomic disorders persisted into adulthood, while epilepsy improved and musculoskeletal problems worsened. In our sample, older patients with R294X and R133C mutations and with C-terminal deletions showed lower levels of clinical severity. The development of guidelines for the clinical management of patients with RTT will assist health care providers in dealing with the complex RTT phenotype. More extensive data about the long-term course of the condition could help in the design of programs for secondary prevention of disabilities for younger females affected by the syndrome. © 2011 Wiley Periodicals, Inc.