This study examined relationships among responsiveness indices for health-related quality of life (HRQOL) measures administered to adults with epilepsy enrolled in an antiepileptic drug trial. The Quality of Life in Epilepsy (QOLIE)-89 was completed at baseline and at a 28-week follow-up. Six responsiveness indices (effect size (ES), standardized response mean (SRM), responsiveness statistic, paired t-test, area under receiver operating characteristic curve or ROC, F-statistic) were calculated for each of the 16 QOLIE-89 scales, using two different external criteria for clinically significant change: (1) attainment of freedom from seizures with altered awareness, and (2) a two-category improvement between baseline and follow-up in a self-rating of the subject's overall condition. Spearman correlations among the six responsiveness indices for the 16 QOLIE-89 scales tended to be moderate to large (Spearman's p = 0.53-1.00; p's < 0.05 for 29 out of the 30 correlations). Rankings of the 16 scales across the two external criteria for change were similar for the responsiveness statistic (Spearman's p = 0.62; p < 0.05), but dissimilar for the other responsiveness indices (all p > 0.05). Both ES and SRM were well predicted by the other indices, except for ROC, using regression modeling. In conclusion, results using different responsiveness indices are comparable for a given external criterion. However, only the responsiveness statistic yielded robust results across two different external criteria. Responsiveness of this HRQOL measure can be reported in terms of previously established benchmarks for ESs, which can be predicted from other indices.