This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over 6 years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use (general practitioner and specialist visits and hospital stays) were summarized into composite scores with principal component analysis. Linear and mixed regression models examined effects of mutation type and other variables on these scores over time. For some mutations (such as p.R255X and p.R168X) health status was poorer at a younger age and improved over time, while for p.R133C it was better at a younger age and deteriorated with time. For those with p.R133C health service use was lowest at a younger age and highest at 25 years. With other mutations, such as p.R255X, p.R270X, p.R294X, C terminal and p.R306C, health service use was higher at a younger age, but dropped off considerably by 25 years of age. Health service use generally declined in parallel with deterioration in health status, although this pattern differed by mutation type, demonstrating important variability in the course of Rett syndrome.