The aim of this study was to investigate the psychometric properties of the Paediatric Quality of Life Inventory (PedsQLTM) in measuring health-related quality of life (HRQOL) and fatigue in adolescents with chronic fatigue syndrome (CFS), using both adolescent-reported and caregiver proxy ratings. Eighty-four participants (42 adolescents and 42 parent proxies) recruited consecutively through CFS specialist clinics at a tertiary paediatric hospital completed the PedsQLTM Core Generic Module (CGM) and Multidimensional Fatigue Scale (MFS). Overall, feasibility, floor/ceiling effects and internal consistency were found to be acceptable for the PedsQLTM CGM and the MFS according to predetermined criteria. For parent–adolescent agreement, intra-class correlations between adolescent and parent report on the PedsQLTM CGM and MFS were statistically significant and rated as ‘fair’ (range 0.45–0.68). At a group level, statistically significant discrepancies between mean adolescent and parent scores for the PedsQLTM CGM were noted on all scales (except school functioning). On the MFS, there were no significant differences between parent and adolescent mean scores. Bland–Altman plots revealed significant variability in the discrepancies between parent and adolescent reports on the PedsQLTM CGM and MFS. Based on the psychometric properties assessment, findings of this study suggest that the parent and adolescent PedsQLTM CGM and MFS are promising scales for use in adolescents with CFS. Parent and adolescent reports offer unique perspectives on HRQOL and fatigue in adolescents with CFS and ideally, reports should be sought from both parties.