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Advances in healthcare, combined with an increasing number of adults with end-stage renal disease (ESRD), mean that there is a growing number of people now surviving on renal replacement therapy. The issue of health-related quality of life (HR-QOL) is becoming increasingly important in this area. For this reason, the content validity of various instruments used to measure HR-QOL in an ESRD population were explored.Systematic searches of MEDLINE (1950–2009) were conducted using terms related to ESRD combined with terms associated with measuring HR-QOL. A total of 378 abstracts were identified, detailing the repeated use of six generic measures and four disease-specific measures. The generic HR-QOL measures discussed include the Medical Outcomes 36-Item Short Form Survey (SF-36), the EuroQOL 5 Dimension (EQ-5D), and the WHO QOL assessment (WHOQOL-BREF). The most frequently used disease-specific measure discussed is the Kidney Disease QOL instrument (KDQOL) and its derivative versions (KDQOL-SF, KDQOL-36).The appropriateness of using the SF-36 in this population is challenged and recommendations include using the WHOQOL-BREF in cases when a generic instrument is required and the KDQOL-SF when a more disease-specific measurement is called for.