Background: PRISM, a novel intervention for adolescents and young adults (AYAs), seeks to enhance resilience skills via four in-person sessions. Primary analysis of the RCT in AYAs with cancer showed PRISM improved HRQOL. This secondary analysis aimed to explore changes in HRQOL domains and differences between patient groups. Methods: English-speaking AYAs (12 - 25 years) were randomized to PRISM or usual care (UC) from Jan 2015 - Oct 2016. Surveys were completed at enrollment and six months later, using the Pediatric Quality of Life Inventory (PedsQL) Generic Short Form (SF-15) and Cancer Module to assess HRQOL. We compared change scores (PRISM vs UC) by domain (PedsQL SF-15: physical, emotional, social, school; cancer: pain, nausea, procedure anxiety, treatment anxiety, worry, cognition, perceived appearance, and communication). Participants were stratified by age (12 - 17 years vs 18 - 25 years) and advanced cancer status (yes/no). Results: 74 patients (36 PRISM, 38 UC) completed 6-month assessments. 72% were 12 - 17 years old. 23% had advanced cancer at enrollment. PRISM improved patient-reported communication (UC: median [interquartile range, IQR] 0 [-17, 8]; PRISM: 8 [0, 25]). Younger patients seemed to benefit more, especially in PedsQL SF-15 school (12 - 17: UC 0 [-8, 0], PRISM 13 [0, 17]; 18 - 25: UC 0 [-33, 17], PRISM 0 [-25, 17]) and social domains (12 - 17: UC 0 [-33, 0], PRISM 0 [0, 8]; 18 - 25: UC 0 [-25, 4], PRISM -17 [-25, 8]), and cancer-specific perceived appearance (12 - 17: UC -4 [-25, 0], PRISM 8 [-8, 25]; 18-25: UC 0 [-21, 0], PRISM -8 [-25, 17]). Patients with advanced cancer seemed to benefit in cancer-specific domains nausea (no: UC 0 [-10, 15], PRISM 10 [-10, 40]; yes: UC 6 [-15, 25], PRISM 35 [25, 50]) and pain (no: UC 13 [-13, 25], PRISM 6 [-13, 25]; yes: UC -13 [-25, 0], PRISM 6 [-13, 25]). Patients without advanced cancer seemed to benefit in perceived appearance (no: UC -6 [-33, 0], PRISM 0 [-8, 17]; yes: UC 0 [-8, 17], PRISM 4 [-8, 17]). Conclusions: With PRISM, younger AYAs were better able to cope with age appropriate challenges (social, school, appearance) and AYAs with advanced cancer improved physical symptom HRQOL. Clinical trial information: NCT02340884