The objective of this article was to describe and illustrate a comprehensive approach for estimating clinically important differences (CIDs) in health-related quality-of-life (HR-QOL). A literature review and pilot study were conducted to determine whether effect size-based benchmarks are consistent with CIDs obtained from other approaches. CIDs may be estimated based primarily upon effect sizes, supplemented by more traditional anchor-based methods of benchmarking (i.e. direct, cross-sectional or longitudinal approaches). A literature review of articles discussing CIDs provided comparative data on effect sizes for various chronic conditions. A pilot study was then conducted to estimate the minimum CID of the Health Utilities Index (HUI) Mark II, and to compare the observed between-group differences observed in a recent randomised trial of an acute stroke intervention with this benchmark. The use of standardised effect size benchmarks has a number of advantages-for example, effect sizes are efficient, widely accepted outside HR-QOL, and have well accepted benchmarks based upon external anchors. In addition, our literature review and pilot study suggest that effect size-based CID benchmarks are similar to those which would be obtained using more traditional methods. For most HR-QOL instruments, we do not know the changes in score which constitute CIDs of various magnitudes. This makes interpretation of HR-QOL results from clinical trials difficult, and having a benchmarking process which is relatively straightforward would be highly desirable.