OBJECTIVE: The lack of a suitable disease-specific, health-related quality of life instrument for dyspepsia prompted the development of the Nepean Dyspepsia Index (NDI). The utility of the NDI in functional dyspepsia is unknown. We aimed to assess the validity of this new quality of life instrument for the first time in United States patients with documented functional dyspepsia. METHODS: The long form of the NDI contains a symptom index and 42 items designed to measure impairment of subjects' ability to engage in and to enjoy relevant aspects of their life because of dyspepsia, as well as a ranking of the individual importance of each aspect. Patients (n = 101, mean age 51 yr, 62% female) who had a history of functional dyspepsia for ≥1 month and a negative endoscopy within the prior 1 yr were followed for 14 days. Patients completed the NDI and the validated Speilberger State- Trait Anxiety Inventory, Beck Depression Inventory, Short Form-36, and a global assessment of symptoms and quality of life at baseline and 14 days later; the NDI was also retested at 48 h and 2 wk. RESULTS: Five clinically relevant factors (subscales), namely, tension/sleep, interference, eating/drinking, knowledge/control, and work/study were identified by factor analysis, after incorporating individual importance ratings (25 items total). All subscales had excellent face validity and internal consistency (Chronbach's α, all >0.85). Reliability was also excellent (intraclass correlations all >0.84). There were modest typically negative correlations between a number of the NDI subscales and the Short Form-36, anxiety, and depression, indicating that the NDI is disease-specific and supporting its validity. Changes in NDI scales correlated moderately with global assessment of change (total score r = -0.49), indicating initial responsiveness. CONCLUSIONS: The Nepean Dyspepsia Index is a valid, disease-specific index for functional dyspepsia, measuring symptoms and health-related quality of life.