Background: Zollinger-Ellison syndrome (ZES) is associated with complicated ulcer disease of the upper gastrointestinal tract. While management of ZES has dramatically improved with proton pump inhibitor therapy, quality of life in medically treated patients has not been evaluated. Methods: Over a 3-year period, 52 patients with ZES were prospectively evaluated at 6-month intervals with upper endoscopy and gastric acid analysis to evaluate the efficacy of current drug therapy and completion of SF36v2 forms. At each 6-month visit, patients' medication and problem lists were reviewed, comorbidities assessed, and any gastrointestinal symptoms recorded. Co-morbidity was represented as a simple illness count for the main analysis. The chronic disease score and the Charlson index were used for sensitivity analyses. Results: The unadjusted norm-based estimate of mental component score (MCS) for 52 patients with ZES (mean age 58, 65% male) was 49.8 (95% CI 46.4, 53.1). The unadjusted estimate of the physical component score (PCS) was 42.3 (95% CI 38.9, 45.7). As the number of illnesses or number of medications increased, there was a monotonic decrease in PCS scores. With multivariable adjustment, the coefficient for number of medications became non-significant. An increase in each of the co-morbidity indexes was associated with a decrease in PCS. Results did not vary by representation of co-morbidity. MCS was not significantly different from the general population. Conclusions: Patients with medically managed ZES have norm-based estimates of the mental component scores as measured by the SF-36v2 that approximate normal values, while the physical component scores were decreased with this reduction largely explained by co-morbid illness. © 2010 Springer Science+Business Media, LLC.