The NIDDK-QA instrument, developed and widely used in liver transplant recipients, assesses quality of life (QOL) in four domains, including liver disease symptoms, physical function, health satisfaction, and overall well-being. We investigated whether the instrument may be used as a disease-specific instrument in ambulatory patients with cholestatic liver disease. The NIDDK-QA instrument was administered in 96 patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) seen at the Mayo Clinic. The SF-36, a well-established generic instrument, was also administered. Standard measures for test-retest reliability, internal consistency, and discriminant and concurrent validity were examined. All patients were ambulatory with mostly normal levels of serum bilirubin and albumin concentrations. The reliability of the NIDDK-QA, as measured by test-retest correlation (Pearson coefficients: 0.82-0.99, P <.01) and by internal consistency (Cronbach's alpha: 0.87-0.94) exceeded conventional acceptability criteria. The correlation between domain scores of the NIDDK-QA and SF-36 was clear and logical in that the physical function domain of NIDDK-QA strongly correlated with the physical component summary score of SF-36 (r = 0.86, P <.01). The overall well-being domain of the NIDDK-QA was closely associated with the mental summary score of SF-36 (r = 0.69, P <.01). Among PBC patients, there was a modest yet significant correlation between the Mayo risk score and overall well-being (r = -0.26, P =.03). In the assessment of QOL in patients with cholestatic liver disease, NIDDK-QA is found reliable and valid. These data, combined with our previous study, demonstrate its applicability in a wide spectrum of disease severity, ranging from early, ambulatory-phase disease to decompensated cirrhosis necessitating liver transplantation.