Paget's disease of bone (PDB) can adversely affect quality of life, but relatively little is known about the clinical predictors of reduced quality of life in patients with the disease. Here, we studied quality of life and its determinants in a large cohort of PDB patients who had been enrolled into the PRISM study, a randomized comparative trial of intensive versus symptomatic treatment for PDB. Health-related quality of life was assessed using the Short-Form 36 (SF36) questionnaire and other validated assessment instruments in 1,324 subjects with PDB. Clinical predictors of quality of life were identified by multivariate regression analysis. The physical summary (mean +/- standard deviation) score of the SF36 was substantially reduced in PDB to 36.3 +/- 11.3 compared with the expected population norm of 50 (P < 0.001). The mental summary score was only slightly reduced, to 48.7 +/- 11.8, in PDB; but this was statistically significant (P < 0.001). Bone pain due to PDB, previous bisphosphonate therapy, and increasing age were identified as negative predictors of the SF36 physical summary score (P < 0.001); but serum levels of total alkaline phosphatase (ALP) did not predict physical summary score. We conclude that PDB has a substantial negative impact on health-related quality of life, which mainly affects physical functioning. The lack of correlation between ALP and quality of life observed in this study emphasizes the importance of addressing quality-of-life issues when treating PDB and not just focussing on response of ALP levels.