Cancer-related symptoms are closely linked to quality of life. The health-related quality of life (HRQoL) is an important outcome for clinical cancer care and oncology research in adolescent cancer survivors. The purpose of this study was to examine HRQoL in adolescents with cancer. With a cross-sectional design, 120 adolescent with cancer were recruited from two medical centers using the SF-36 HRQoL, the M. D. Anderson Symptom Inventory, and Karnofsky Performance Scale. Major finding: 1. The role-physical domain of HQoL received the lowest score in adolescent cancer patients, and bodily pain domain of HQoL received the highest score. 2. Adolescence who were receiving cancer treatment had significantly poorer HRQoL than the off-treatment group. 3. The health-related quality of life Mean scores were significantly positively correlated with performance status and hemoglobin levels. 4. Older survivors showed a lower levels of HRQoL. The results from this study assist clinicians better understanding the status of quality of life and provide important implications in promoting quality of life for adolescents with cancer.