OBJECTIVES: Although several health-related quality of life (HRQOL) instruments exist for adult cancer survivors, little attention has been paid to identify appropriate instruments for young adult survivors of childhood and adolescent cancer (YASCAC).  We aim to make head-to-head comparisons of 3 HRQOL instruments for YASCAC. METHODS: We collected data via telephone interviews between 05/01/2009 and 09/30/2009 from 141 YASCAC who were off therapy at least 2 years without cancer and enrolled in the CSP and/or the UF Tumor Registry.  Each subject reported his/her late effects (yes/no) and HRQOL.  HRQOL was measured using the Quality of Life in Adult Cancer Survivor (QLACS), Quality of Life-Cancer Survivor (QOL-CS), and SF-36.  We used Cronbach’s alpha coefficient to estimate reliability.  We estimated Pearson’s correlation coefficients to examine convergent/discriminant validity.  We hypothesized homogenous domains (e.g., physical functioning and pain) among 3 instruments would be strongly correlated with each other compared to heterogeneous domains (e.g., physical vs. psychological functioning).  We used effect sizes to evaluate late effect known-groups validity which is the extent to which HRQOL scores differ by late effects (yes/no). RESULTS: Cronbach’s alpha coefficients were acceptable (>0.7) for all domains.  Physical domains of the QLACS (e.g., pain) were strongly correlated with the SF-36’s physical component summary (PCS), but weakly with mental component summary (MCS).  Mental domains of the QLACS (e.g., negative feelings) were strongly correlated with MCS, but weakly with PCS.  However, both physical and mental domains of the QOL-CS were strongly correlated with MCS compared to with PCS, suggesting poor convergent/discriminant validity.  Effect sizes suggest greater discrimination (>0.5) by the QOL-CS and SF-36 for late effect known-groups compared to the QLACS. CONCLUSIONS: The 3 HRQOL instruments are not superior to each other.  We suggest using item response theory to select high quality items from different instruments to measure HRQOL for YASCAC more meaningfully.