Background Disease registries are an important source of information on the natural history of rare diseases and the response to new therapies in a real-world setting. The value of the information, however, is directly related to the completeness of the data entered for each patient over the course of time. The Fabry Outcome Survey (FOS) is a Shire Human Genetic Therapies–sponsored, physician-directed registry of patients with Fabry disease, a rare, multisystem, lysosomal storage disorder, established in 2001. Objective and Methods In 2005, measures were introduced to improve the completeness of data capture, including a focus on centers with 20 or more patients enrolled in the FOS, concentration on a limited number of core variables (i.e., serum creatinine, urinary protein, left ventricular mass [echocardiography], blood pressure [systolic and diastolic], pain, quality of life, and other Fabry disease–related signs and symptoms, as well as height and weight) and the introduction of Clinical Project Associates (CPAs) to facilitate data management by participating treatment centers. Results An analysis of random samples of approximately 25% of patients in the registry in 2008 showed significant increases in data capture for most of the core variables examined. Conclusions We conclude that the measures introduced in 2005 significantly improved the value of the information in the registry, which has contributed greatly to our understanding of patients' real-world experience with enzyme replacement therapy for Fabry disease.