Purpose: Adolescents with cancer (aged 12-18 years) are at risk for impaired health-related quality of life (HRQoL). Little is known about this population during treatment. This study aimed to (1) determine the HRQoL of adolescents with cancer during the first year of treatment and compare them with age-matched peers and (2) obtain insight into cancer-specific HRQoL of adolescents during the first year of treatment. Methods: Participants were part of a larger study focused on routine monitoring of electronic reported outcomes in standard pediatric oncology care. Adolescents completed the pediatric quality of life inventory (PedsQL) 4.0 and the PedsQL Cancer Module 3.0. Mean generic HRQoL scale scores were compared between the groups using multivariate analysis of covariance. Cancer-specific item scores were dichotomized and percentages were calculated to determine the proportion of adolescents reporting presence or absence of problems. Results: A total of 73 (mean [M]age = 14.71, standard deviation [SD] = 1.85) adolescents with cancer (Mage = 14.71, SD = 1.85, Mtimesincediagnosis = 3.51 months, SD = 2.8) and 268 healthy peers (Mage = 14.23, SD = 1.51) participated. Adolescents with cancer reported significantly lower generic HRQoL scores on all domains than their peers (p's <0.05, η2 = 0.01-0.42). Most frequently reported cancer-specific HRQoL problems were pain (hurt joint/muscle, 42.9%), nausea (during medical treatments [47.1%]; food not tasting good [54.3%]; food and smells [61.4%]), worry (about relapse [45.7%]; about side effects [52.9%]), cognitive problems (paying attention [47.1%]), and physical appearance (not good looking [47.1%]). Conclusions: Adolescents with cancer showed impaired HRQoL during treatment on both physical and psychosocial domains. Close monitoring of physical and psychosocial symptoms during treatment is, therefore, important.