Children with thalassemia major must be treated with life-long blood transfusions. Evidence suggests that patients with more knowledge/information about their illnesses adhere more readily to treatment schedules. However, there has been little evaluation of disease knowledge and treatment adherence in thalassemia major children. The objectives of the current study were to detect factors affecting the compliance of thalassemic children and their mothers and to identify the relationships between disease knowledge and treatment adherence in thalassemic children. A cross-sectional descriptive design and purposive sampling were used. fifty thalassemia major children (mean age 13.74 years) and their 50 mothers were recruited. structured questionnaire consisting of (A) personal Information; included, Socio-demographic and disease-related data were collected which included age, gender, educational level, (b) An assessment of disease knowledge about TM ; Assessment of disease knowledge of children and their mothers consisted of 20 open questions measuring children's and mothers' knowledge, treatment and compliance of treatment plan about TM. The result of this study revealed that that moderate commitment was apparent in 6% of sample with week knowledge and 60% of sample with moderate knowledge while, strong commitment was found in 26% of sample with moderate knowledge and in 8% of them with week knowledge. This relation was highly statistically significant (p= .000).Based on the findings of the current study, it can be concluded that, The positive association between knowledge about disease and treatment adherence and factors of patients’ knowledge indicate the need for systematic education for patients and caregivers to improve their compliance with treatment. The current study recommended that, the improvement of the quality of patient care, reinforcement of medical education and enhanced efforts by clinical staff to provide practical knowledge to children with thalassemia major and their parents is mandatory to significantly improve patient compliance to treatment.