OBJECTIVES: ADPKD imposes substantial burdens on HRQoL at all stages of the disease. Few studies have examined disease impacts and symptomatology on HRQoL. This analysis aimed to assess whether disease-specific questionnaires allow for improved assessment of HRQoL in ADPKD. METHODS: In a large global observational study of 3,409 subjects, patient-reported outcomes (PRO) instruments (including SF-12v2, EQ-5D, ADPKD-IS) were completed in 6-month intervals. Scores were calculated at Baseline and longitudinally, overall and by chronic kidney disease (CKD) stage. RESULTS: The overall population scores were normal/near normal regardless of instrument with little change overtime (mean score at Baseline and 18 months): SF-12 Mental Component Summary score (MCS) 50.15 to 49.77, SF-12 Physical Component Summary score (PCS) 49.94 to 49.12; EQ-5D US Index 0.91 to 0.90; ADPKD-IS Physical 1.59 to 1.66, Emotional 1.78 to 1.79, Fatigue 1.90 to 1.95. Only the SF-12 PCS and ADPKD-IS instruments were able to differentiate between early and late stage disease at Baseline (CKD1 vs CKD4 at baseline (SD): PCS 52.22 (8.41) vs 46.79 (9.89), MCS 49.66 (9.90) vs 51.09 (9.63), EQ-5D US Index 1.06 (0.25) vs 1.13 (0.34), ADPKD-IS Physical 1.47 (0.82) vs 1.83 (0.88), Emotional 1.72 (0.88) vs 2.07 (0.91), Fatigue 1.77 (1.03) vs 2.25 (1.23)). Longitudinal changes (Baseline and 18 months) could only be measured in later disease stages. Changes in EQ-5D and SF-12 were driven by impacts on overall health state. CONCLUSIONS: The disease-specific ADPKD-IS questionnaire was more sensitive to HRQoL in a cross-sectional analysis by disease severity vs all generic HRQoL instruments except SF-12 PCS. In a slowly progressing disease like ADPKD, observations of longitudinal change in HRQoL will require longer follow-up.  These results support that ADPKD disease impacts are incapable of being measured by blunt generic tools.