This study aimed to identify health-related quality of life (HRQoL) issues of relevance for adolescent and young adult (AYA) cancer patients, the perception of relevant HRQoL issues for AYA in generalby the health care professionals (HCP), and discrepancies between issues identified by AYAs and HCP. Dutch AYAs aged 18–35 years at the time of cancer diagnosis (N = 83) and HCPs (N = 34) involved in AYA oncology were invited to complete the Quality of Life for Cancer Survivors questionnaire. HCPs rated physical symptoms such as fatigue, appetite, pain, constipation, sleep disorders, nausea and neuropathy among AYA cancer patients significantly higher (i.e., more problems) than AYA cancer patients. AYA cancer patients rated overall physical health and quality of life, happiness, satisfaction, usefulness and support from others, all positively formulated questions, significantly higher (i.e., more positive) than HCPs. The most highly rated issues (negative and positive combined) for AYAs were: perceived support from others, distress about initial cancer diagnosis, distress for family and overall quality of life. HCPs identified distress about diagnosis, treatment, family and interference of illness with employment/study as the most problematic issues (all negative) for AYAs. Five of the ten most common issues listed by patients and HCPs were the same. Male AYAs, patients treated with curative intent and those with a partner rated positive HRQoL issues higher than their counterparts. The discrepancy between the perception of patients and HCPs illustrates the importance of patient involvement in organizing physical and psychosocial care.