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Objective The objectives of this study were to determine whether a measure of global self-concept demonstrated longitudinal measurement invariance between adolescents aged 10–19 years with and without chronic illness and to document differences in their global self-concept trajectories over time. Methods Data were obtained from the National Longitudinal Survey of Children and Youth (N = 10,064). Global self-concept was measured using a scale based on the Self-Determination Questionnaire. Results 16 percent of adolescents had chronic illness. There was evidence of partial longitudinal invariance in global self-concept between adolescents with and without chronic illness. Controlling for sociodemographic characteristics, adolescents with a chronic illness exhibited lower levels of global self-concept and more precipitous declines over time. Conclusions The results from this study suggest that comparisons of global self-concept between adolescents with and without chronic illness are meaningful and, compared to healthy controls, adolescents with chronic illness are at risk for low global self-concept.