Background: Measurement properties of a generic instrument to assess health-related quality of life in patients with chronic pancreatitis have not been described. Methods: We assessed the health-related quality of life in 314 patients with chronic pancreatitis using the generic Medical Outcomes Study Short Form-36 Health Survey. Data were compared with age- and gender-matched general population norms and the psychometric properties of the instrument were evaluated. Results: Patients with chronic pancreatitis reported considerably worse scores on all Short Form-36 scales compared with the general population. Decrements were most pronounced in role limitations caused by physical (-29%) and emotional health problems (-20%), and general health perceptions (-19%). Test-retest reliability coefficients were ≥0.82 for all subscales and internal consistency coefficients ranged from 0.78 to 0.92. Floor effects were negligible for all but the two role subscales, but there were substantial ceiling effects for five of the eight subscales. Construct validity was supported by the findings that the Short Form-36 discriminated well between patients of different age, burden of chronic illness and severity of symptoms. Conclusions: Patients with chronic pancreatitis experience substantial deteriorations in health-related quality of life compared with the general population. The Short Form-36 proved to be a feasible, reliable and valid measure for descriptive studies of patients with chronic pancreatitis, but ceiling effects may limit its usefulness as an outcome measure in the assessment of treatment effects.