Sickle cell disease (SCD) complications place patients at risk for poor psychosocial adaptation, including depression and anxiety symptoms. This study aimed to test a mediator model based on the Risk and Resistance model to explore the role of intrapersonal characteristics and stress processing variables in psychosocial functioning. Participants were 44 adolescents with SCD, 15 healthy siblings, and 43 primary caregivers, recruited from an East Coast comprehensive sickle cell center. The participants completed paper and pencil measures of resilience factors (attributional style, hope, coping) and internalizing symptoms (depression, anxiety). Internalizing symptoms among adolescents with SCD and healthy siblings did not differ and were within non-clinical ranges. Self-esteem of adolescents with SCD was correlated with less depression and anxiety and sense of inadequacy was associated with poorer functioning. There were no findings to support the role of coping in psychosocial adjustment. Although the mediation hypothesis was not supported, findings highlighted the resilience of this sample of adolescents with SCD. Determining how these resilience factors protect adolescents with SCD may aid in the development of psychosocial interventions. In particular, interventions should focus on improving intrapersonal skills and coping with stress and investigate ways to tailor these interventions to African-American populations.