Abstract Background: Congenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation in children. Compliance to medication in patients with CH is known to improve the neurodevelopmental outcomes of CH. Compliance to therapy can be affected by multiple factors. Aim of the work: The aim of this study is to explore compliance of the patients and/or their target families to therapy of CH, and to explore factors affecting compliance to medication in patients with CH. Subjects and Methods: This was descriptive cross- sectional study, which was conducted in Endocrinology and Pediatric Outpatient Clinics in Sharkia Governorate health insurance center, Egypt. The study participants were 120 newborn and infant with CH and their mothers. Data were collected using multi-structured questionnaires for determining socioeconomic state, clinical picture of congenital hypothyroidism, personal, family history and Morisky Medication Adherence Scale 8 (MMAS 8) to assess patient compliance. Results: About two third of patient families were highly compliant to therapy. Compliance to therapy was affected by multiple factors including occupational and educational levels of the parents, residence, income, social class, presence of symptoms and associated congenital anomalies. Binary logistic regression of factors affecting patient’s compliance showed that the most significant factors affecting compliance were mother’s education, social class and presence of symptoms at presentation. Conclusion: Compliance to L thyroxin therapy in our patients and/or their family was found to be reasonable and affected by multiple factors namely mother’s education, social class and presence of symptoms at presentation. Keywords: Congenital Hypothyroidism; Compliance; Medication Adherence