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Summary Objective The aim of this study was to examine measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) across age, sex, and time in a representative sample of children with newly diagnosed epilepsy. Methods Data come from 373 children enrolled in the Health-related Quality of Life in Children with Epilepsy Study (HERQULES), a multisite prospective cohort study. Measurement equivalence was examined using a multiple-group confirmatory factor analysis framework, whereby increasingly stringent parameter constraints are imposed on the model. Comparison groups were stratified based on age (4-7 years vs. 8-12 years), sex (male vs. female), and time (measurement of health-related quality of life at diagnosis vs. 24 months later). Results The QOLCE-55 demonstrated measurement equivalence at the level of strict invariance for each model tested - age: χ2 (3,123) = 4,097.3, p < 0.001; Comparative Fit Index (CFI) = 0.968; Root Mean Square Error of Approximation (RMSEA) = 0.042 (0.038, 0.045); sex: χ2 (3,124) = 4,188.3, p < 0.001; CFI = 0.964; RMSEA = 0.044 (0.040, 0.047); and time: χ2 (3,121) = 5,185.0, p < 0.001; CFI = 0.965; RMSEA = 0.046 (0.043, 0.048). Significance These findings suggest that items comprising the QOLCE-55 are perceived similarly among groups stratified by age, sex, and time and provide further evidence supporting the validity of the scale in children with epilepsy. Health professionals and researchers should be confident that group comparisons made using the QOLCE-55 are unbiased and that any group differences detected are meaningful; that is, not related to differences in the interpretation of items by informants. Future research replicating these findings is encouraged.