Background: Thalassemia a serious, life-limiting disease that can be life-threatening and cause great disruption in all dimensions of life. Aim: This study aimed to evaluate stress, anxiety and depression in adolescents with thalassemia. Subjects and Method: Design: A descriptive research design was utilized. Setting: Pediatric Hospital in Mansoura University and an inpatient department of El- Tadamon Hospital in Port-Said city. Subjects: The studied subjects consisted of 112 adolescents whom selected from above mentioned settings. Tools:  Data were collected through Depression Anxiety Stress Scale (DASS21), in addition to personal and clinical data questionnaire. Results: The study revealed that, approximately half of the studied adolescents (48.2%) had extremely severe level of stress, more than half of them (54.5%) had extremely severe level of anxiety, and less than one quarter of them (23.2%) had extremely severe level of depression. Conclusion: Adolescents suffering from thalassemia are exposed to multiple health problems especially what related to psychological and emotional dimensions represented in severe anxiety and stress. Recommendations: The main recommendation was designing and applying continuous educational programs for adolescents with thalassemia regarding their disease to maintain compliance to the therapeutic regimen and prevent negative impacts of thalassemia on their psychological status. These programs should be led by health professionals.