Objective: Medical factors that put adolescents and young adults (AYA) with epilepsy at risk for poor health-related quality of life (HRQOL) are well-established. Less known is whether medical risk is associated with decreases in global psychological well-being and how self-management self-efficacy might contribute to resilience. The current study seeks to (a) examine the relationship between medical risk and both HRQOL and psychological well-being in AYA with epilepsy and (b) investigate the potential moderating role of self-management self-efficacy. Methods: A sample of 180 AYA with epilepsy, aged 13-24 years, was recruited from clinic and community settings and completed questionnaires. A medical risk gradient composed of seizure frequency, antiepileptic drugs, and other health problems was created. HRQOL, psychological well-being, and self-management self-efficacy were assessed. Results: Medical risk was negatively associated with HRQOL, such that youth with greater risk scores reported lower HRQOL (r = -0.35, p <. 01). However, there was no significant relationship between medical risk and psychological well-being (r = -0.08, p =. 31). Self-efficacy was positively correlated with HRQOL and well-being (r = 0.50, p <. 01; r = 0.48, p <. 01). A moderation effect was detected, such that the positive effect of self-efficacy on HRQOL differed across medical risk levels. Implications: Cultivating psychological strengths, as opposed to solely addressing medical problems, may be a promising intervention target when treating AYA with epilepsy, including those navigating healthcare transitions. Self-efficacy predicted HRQOL at most levels of risk, suggesting an important modifiable intrinsic factor that may promote resilience.