The psychometric properties of a disease-specific instrument used to assess self-efficacy in adolescents with sickle cell disease, the Sickle Cell Self-Efficacy Scale, were evaluated in a sample of 131 adolescents ranging from 11 to 19 years of age. This nine-item instrument was associated with a one-item, general self-efficacy question and an item of self-control. After controlling for age, gender, highest grade of education completed, and the number of individuals in the household, high levels of self-efficacy were related to fewer physical, psychological, and total symptoms. Using the stress process framework to examine the relationship between self-efficacy and self-reported symptoms in adolescents may lead to the initiation of effective intervention programs capable of increasing levels of self-efficacy in adolescents. These interventions could lead to better outcomes for adolescents with sickle cell disease. Additional longitudinal investigations are needed to evaluate the ability of self-efficacy to predict adolescent adjustment over time.