Although measuring health-related quality of life (HRQoL) in adolescents with cancer helps clinicians to personalize care for their patients, no previous studies have included HRQoL measurement at the time of diagnosis of osteosarcoma (OS) or acute myeloid leukemia (AML). The purpose of this study was to evaluate the feasibility of measuring adolescents' HRQoL at the time of their diagnosis of OS or AML, and to compare their ratings with those of their parents and of similarly diagnosed but younger patients aged 8- to 12- years. Participants included 126 patients (79 adolescents) and 130 parents (78 parents of adolescents); most completed the HRQoL instrument/s within 48 hours of the first chemotherapy cycle. Ninety-three percent of adolescents diagnosed with OS and 93% of those diagnosed with AML completed the HRQoL instruments. Agreement between the adolescents and their parents ranged from 0.29 to 0.71 (OS) and 0.44 to 0.62 (AML). In all domains, OS adolescents had significantly lower PedsQL v.4.0 scores than adolescents with AML. Our findings demonstrates the feasibility of measuring HRQoL in adolescents with OS or AML (and their parents) at the time of diagnosis, and thus their HRQoL ratings can be used to inform their cancer care from diagnosis forward.