Objective: The present study aimed to evaluate the efficacy of Op Koers Online, a protocolled online psychosocial group intervention for adolescents with a chronic illness (CI). Methods: Adolescents (12–18 years) with different types of CI (N = 59; Mean age = 15.1 years, SD = 1.7; 54% female) participated in a parallel multicenter randomized controlled trial comparing Op Koers Online (N = 35) with a waitlist control group (N = 24). Assessments (online questionnaires) took place at baseline (T0), 6-months (T1) and 12-months follow-up (T2). Primary outcomes were internalizing and externalizing behavioral problems and disease-related coping skills. Health-Related Quality of Life was secondary. Efficacy was tested with linear mixed models. Results: Compared to the control group, the intervention had a significant positive effect (p < .05) on disease-related coping skills T1 vs T0 (use of relaxation, β = 0.68; social competence, β = 0.57) and T2 vs T0 (information seeking, β = 0.61), and on HRQoL (social-, school-, psychosocial functioning and total HRQoL) T1 vs T0 (β = 0.52 to β = 0.60). No intervention effects on internalizing and externalizing behavioral problems were found. Conclusion: The results of this randomized controlled trial indicate a positive effect of Op Koers Online. The intervention had beneficial effects on disease-related coping skills and HRQoL. Practice implications: The next step is to implement Op Koers Online for adolescents in clinical practice.